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Endometriosis dan endoglin 2011.

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Reference Type: Journal Article

Record Number: 39

Estrogen therapy for hereditary haemorrhagic

telangiectasia (HHT): Effects of raloxifene, on
Endoglin and ALK1 expression in endothelial cells
Year: 2010

Author: V. Albinana, M. E. Bernabeu-Herrero, R. Zarrabeitia, C. Bernabeu and L.

M. Botella

Journal: Thromb Haemost

Volume: 103
Issue: 3
Pages: 525-34

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is

an autosomal dominant vascular disease. The clinical manifestations are epistaxis,
mucocutaneous and gastrointestinal telangiectases, and arteriovenous
malformations. There are two predominant types of HHT caused by mutations in
Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1
and HHT2, respectively. No cure for HHT has been found and there is a current
need to find new effective drug treatments for the disease. Some patients show
severe epistaxis which interferes with their quality of life. We report preliminary
results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women
diagnosed with osteoporosis. We tried to unravel the molecular mechanisms
involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for
proteins involved in the transforming growth factor beta pathway and it is widely
accepted that haploinsufficiency is the origin for the pathogenicity of HHT.
Therefore, identification of drugs able to increase the expression of those genes is
essential to propose new therapies for HHT. In vitro results show that raloxifene
increases the protein and mRNA expression of ENG and ALK1 in cultured
endothelial cells. Raloxifene also stimulates the promoter activity of these genes,
suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene
improved endothelial cell functions like tubulogenesis and migration in agreement
with the reported functional roles of Endoglin and ALK1. Our pilot study provides a
further hint that oral administration of raloxifene may be beneficial for epistaxis
treatment in HHT menopausal women. The molecular mechanisms of raloxifene
involve counteracting the haploinsufficiency of ENG and ALK1.

Reference Type: Journal Article

Record Number: 36
Endometriosis dan endoglin 2011.enl Page 2

Dynamic expression of Endoglin, a TGF-beta

co-receptor, during pre-circulation vascular
development in chick
Year: 2010

Author: C. Alev, B. A. McIntyre, K. Ota and G. Sheng

Journal: Int J Dev Biol

Volume: 54
Issue: 4
Pages: 737-42

Mutations in the human Endoglin gene, encoding a dimeric TGF-beta co-receptor,

lead to type 1 hereditary hemorrhagic telangiectasia. Studies in mice have revealed
important roles of Endoglin in endothelial cell proliferation, differentiation and
integrity. Endoglin(-/-) mouse embryos die at mid-gestation due to cardiac defects
and vessel rupture. Its role during early vasculogenesis is unclear, as the initial
phase of vascular endothelial cell formation appears unaffected in Endoglin(-/-)
embryos. In order to understand possible roles of Endoglin in early vascular
development, we used the chick model and analyzed the temporal and spatial
expression pattern of Endoglin during vasculogenesis in pre-circulation stage chick
embryos. Weak Endoglin expression was detected at HH4 in the node and in the
extraembryonic mesoderm. The node-specific expression is transitory and
disappears after HH5. Strong up-regulation of Endoglin expression is seen at HH8
in all endothelial progenitors undergoing morphological changes to become
endothelial cells. Most extraembryonic splanchnopleural vascular endothelial cells
down-regulate Endoglin after their morphological differentiation, whereas lateral
plate and cardiac endothelial cells remain positive until HH12, followed by a clear
drop after circulation starts at HH13. Progenitors for the pronephric duct are positive
from HH10 to HH12, but down-regulate Endoglin after epithelialization of duct cells.
Overall, these data reveal a dynamic expression pattern of Endoglin in
pre-circulation chick development and indicate that Endoglin may play an important
role in the transition from endothelial progenitors to functional endothelial cells
during early vascular development.

Reference Type: Journal Article

Record Number: 52

Cellular basis of diabetic nephropathy: V. Endoglin

expression levels and diabetic nephropathy risk in
patients with Type 1 diabetes
Year: 2010
Endometriosis dan endoglin 2011.enl Page 3

Author: P. Alvarez-Munoz, M. Mauer, Y. Kim, S. S. Rich, M. E. Miller, G. B. Russell,

J. M. Lopez-Novoa and M. L. Caramori

Journal: J Diabetes Complications

Volume: 24
Issue: 4
Pages: 242-9

Endoglin is an accessory receptor molecule that, in association with transforming

growth factor beta (TGF-beta) family receptors Types I and II, binds TGF-beta1,
TGF-beta3, activin A, bone morphogenetic protein (BMP)-2 and BMP-7, regulating
TGF-beta dependent cellular responses. Relevant to diabetic nephropathy,
endoglin, expressed in vascular endothelial and smooth muscle cells, fibroblasts,
and mesangial cells, negatively regulates extracellular matrix (ECM). The aim of this
study was to evaluate endoglin expression in cultured skin fibroblasts from patients
with Type 1 diabetes with and without diabetic nephropathy. Kidney and skin
biopsies were performed in 125 Type 1 diabetic patients. The 20 with the fastest
rate of mesangial expansion (estimated by electron microscopy) and proteinuria
("fast-track") and the 20 with the slowest rate and normoalbuminuria ("slow-track"),
along with 20 controls were studied. Endoglin mRNA expression was assessed by
microarray and quantitative real-time polymerase chain reaction (QRT-PCR) and
protein expression by Western blot. Age and sex distribution were similar among
groups. Diabetes duration was similar (20+/-8 vs. 24+/-7 years), hemoglobin A1c
lower (8.4+/-1.2% vs. 9.4+/-1.5%), and glomerular filtration rate higher (115+/-13 vs.
72+/-20 ml/min per 1.73 m2) in slow-track vs. fast-track patients. Microarray
endoglin mRNA expression levels were higher in slow-track (1516.0+/-349.9) than
fast-track (1211.0+/-274.9; P=.008) patients or controls (1223.1+/-422.9; P=.018).
This was confirmed by QRT-PCR. Endoglin protein expression levels correlated with
microarray (r=0.59; P=.044) and QRTPCR (r=0.61; P=.034) endoglin mRNA
expression. These studies are compatible with the hypothesis that slow-track Type 1
diabetic patients, strongly protected from diabetic nephropathy, have distinct cellular
behaviors that may be associated with reduced ECM production.

Reference Type: Journal Article

Record Number: 26

Endoglin: A marker of neoplasias or rather of

Year: 2010

Author: V. Barresi and G. Barresi

Journal: Head Neck

Volume: 32
Issue: 7
Pages: 970-1; author reply 971
Endometriosis dan endoglin 2011.enl Page 4

Reference Type: Journal Article

Record Number: 14

Abnormal expression of Endoglin and its receptor

complex (TGF-beta1 and TGF-beta receptor II) as
early angiogenic switch indicator in premalignant
lesions of the colon mucosa
Year: 2010

Author: G. Bellone, C. Gramigni, B. Vizio, F. A. Mauri, A. Prati, D. Solerio, L.

Dughera, E. Ruffini, G. Gasparri and M. Camandona

Journal: Int J Oncol

Volume: 37
Issue: 5
Pages: 1153-65

The precise timing of the angiogenic switch in colorectal cancer development is still
unclear. The simultaneous expression of Endoglin (CD105), transforming growth
factor (TGF)-beta1 and TGF-beta receptor (R) II were quantified in surgical
specimens comprising normal human colon, pre-malignant dysplastic tissue, in situ,
and invasive colon cancer specimens, at mRNA and protein levels, respectively by
real-time PCR and immunohistochemistry. Serum concentrations of soluble
Endoglin and TGF-beta1 were evaluated. mRNA and CD105+-microvessel density
(MVD) increased significantly in dysplastic colon and carcinoma versus normal
tissues; values correlated respectively with dysplasia degree and Dukes' stages.
TGF-beta1 expression was significantly upregulated in most severe dysplastic
adenoma specimens, while TGF-beta1 transcript and protein signals were intense in
carcinoma, positively-correlated with tumor progression. TGF-beta1 RII was
overexpressed in adenoma and carcinoma versus normal samples, but unrelated
with dysplasia or Dukes' stage. Soluble Endoglin serum levels were equivalent in
adenoma and normal tissues; in carcinoma the highest levels were in invasive
tumor. Circulating TGF-beta1 levels were increased in severe dysplasia and
progressed with tumor progression. Correlations between adenoma dysplasia
degree and TGF-beta RII and CD105+-MVD, and between tumor Dukes' staging
and TGF-beta1 and CD105+-MVD, were significant. TGF-beta1 and Endoglin and
TGF-beta1 serum levels, TGF-beta1 staining and CD105+-MVD were significantly
and inversely associated with disease-free survival. TGF-beta1 levels were an
independent and significant prognostic factor of disease-free survival. These
findings suggest active angiogenesis occurs in many pre-malignant colon cases and
supports more careful evaluation of different chemopreventive agents.
Endometriosis dan endoglin 2011.enl Page 5

Reference Type: Journal Article

Record Number: 3

Increased plasma soluble endoglin levels as an

indicator of cardiovascular alterations in
hypertensive and diabetic patients
Year: 2010

Author: A. M. Blazquez-Medela, L. Garcia-Ortiz, M. A. Gomez-Marcos, J. I.

Recio-Rodriguez, A. Sanchez-Rodriguez, J. M. Lopez-Novoa and C.

Journal: BMC Med

Volume: 8
Pages: 86

BACKGROUND: Endoglin is involved in the regulation of endothelial function, but

there are no studies concerning its relation with hypertension- and
diabetes-associated pathologies. Thus, we studied the relationship between plasma
levels of soluble endoglin and cardiovascular alterations associated with
hypertension and diabetes. METHODS: We analyzed 288 patients: 64 with type 2
diabetes, 159 with hypertension and 65 healthy patients. We assessed the
relationship of soluble endoglin plasma levels measured by enzyme-linked
immunosorbent assay with basal glycemia, glycosylated hemoglobin, blood
pressure, endothelial dysfunction (assessed by pressure wave velocity),
hypertensive retinopathy (by Keith-Wagener classification), left ventricular
hypertrophy (by Cornell and Sokolow indexes), cardiovascular risk and target organ
(heart, vascular, kidney) damage. RESULTS: There are significant correlations
between endoglin and glycemia, systolic blood pressure, pulse pressure, pressure
wave velocity and electrocardiographically assessed left ventricular hypertrophy.
Endoglin levels were significantly higher in patients with diabetes who had
nondipper and extreme dipper circadian blood pressure patterns than in dipper
circadian patterns, in patients with hypertension and diabetes who had riser pattern
than in the other patients, and in patients with diabetes but not hypertension who
had extreme dipper pattern than in dipper, nondipper and riser groups. There was
also a significant correlation between plasma-soluble endoglin and lower levels of
systolic night-day ratio. Higher endoglin levels were found in patients with diabetes
who had retinopathy, in patients with diabetes who had a high probability of 10-year
cardiovascular risk, and in patients with diabetes and hypertension who had three or
more damaged target organs (heart, vessels, kidney) than in those with no organs
affected. CONCLUSIONS: This study shows that endoglin is an indicator of
hypertension- and diabetes-associated vascular pathologies as endothelial
dysfunction and cardiovascular damage.
Endometriosis dan endoglin 2011.enl Page 6

Reference Type: Journal Article

Record Number: 45

The role of urinary soluble endoglin in the

diagnosis of pre-eclampsia: comparison with
soluble fms-like tyrosine kinase 1 to placental
growth factor ratio
Year: 2010

Author: C. S. Buhimschi, M. A. Baumbusch, A. T. Dulay, S. Lee, M. Wehrum, G.

Zhao, M. O. Bahtiyar, C. M. Pettker, U. A. Ali, E. F. Funai and I. A. Buhimschi

Journal: BJOG
Volume: 117
Issue: 3
Pages: 321-30

OBJECTIVE: Endoglin, an anti-angiogenic glycoprotein expressed on endothelial

cells, has been proposed recently as a biomarker of pre-eclampsia (PE). Given that
PE is characterised by an imbalance of angiogenic factors, we sought to determine
the clinical utility of urinary soluble endoglin, relative to the soluble fms-like tyrosine
kinase 1 to placental growth factor (PlGF) ratio, in the diagnosis of PE during
gestation. DESIGN: Prospective observational cohort. SETTING: Tertiary referral
university hospital. POPULATION: Two hundred and thirty-four pregnant women
were enrolled prospectively in the following groups: healthy controls, n = 63;
gestational age (GA), median (interquartile range), 33 weeks (27-39 weeks); chronic
hypertension, n = 27; GA, 33 weeks (30-36 weeks); mild PE, n = 38; GA, 37 weeks
(34-40 weeks); severe PE, n = 106; GA, 32 weeks (29-37 weeks). METHODS: Free
urinary levels of soluble endoglin, soluble fms-like tyrosine kinase 1 and PlGF were
measured by sensitive and specific immunoassay. Levels for all urinary analytes
were normalised to creatinine. MAIN OUTCOME MEASURES: Urinary soluble
endoglin, and the soluble fms-like tyrosine kinase 1 to PlGF ratio. RESULTS: In
healthy controls, urinary soluble endoglin levels were increased significantly at term
relative to those earlier in gestation. Severe PE was characterised by an increased
urinary level of soluble endoglin, soluble fms-like tyrosine kinase 1, protein to
creatinine ratio and soluble fms-like tyrosine kinase 1 to PlGF ratio compared with
all other groups. There was a direct correlation between urinary soluble endoglin
and proteinuria that remained after GA correction (R = 0.382, P < 0.001). Urinary
soluble endoglin could not differentiate mild PE from severe preterm PE. Overall,
soluble endoglin had the ability to discriminate PE from chronic hypertension and
healthy controls only in women who were evaluated at <37 weeks of GA. The
sensitivity, specificity and accuracy of urinary soluble endoglin alone in the
diagnosis of PE or in the identification of women with PE requiring a mandated
delivery before 37 weeks of gestation were 70%, 86% and 76%, respectively. These
values were inferior to those of the soluble fms-like tyrosine kinase 1 to PlGF ratio
(P < 0.001). The addition of urinary soluble endoglin did not improve the diagnostic
accuracy of the soluble fms-like tyrosine kinase 1 to PlGF ratio alone.
Endometriosis dan endoglin 2011.enl Page 7

CONCLUSIONS: We have provided evidence that soluble endoglin is present and

elevated in the urine of women who develop preterm PE. Urinary soluble endoglin
has only limited ability to determine the severity of PE and to distinguish between
PE and chronic hypertension both preterm and at term. Compared with urinary
soluble endoglin, the soluble fms-like tyrosine kinase 1 to PlGF ratio remains a
better marker of disease presence, severity and outcome.

Reference Type: Journal Article

Record Number: 28

Endoglin negatively regulates transforming growth

factor beta1-induced profibrotic responses in
intestinal fibroblasts
Year: 2010

Author: J. P. Burke, R. W. Watson, J. J. Mulsow, N. G. Docherty, J. C. Coffey and

P. R. O'Connell

Journal: Br J Surg
Volume: 97
Issue: 6
Pages: 892-901

BACKGROUND: Fibroblasts isolated from strictures in Crohn's disease (CD) exhibit

reduced responsiveness to stimulation with transforming growth factor (TGF) beta1.
TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated
intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of
TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular
biopsies of patients undergoing intestinal resection for CD strictures or from control
patients. Endoglin expression was assessed using confocal microscopy, flow
cytometry and western blot. The effect of small interfering (si) RNA-mediated
knockdown and plasmid-mediated overexpression of endoglin on fibroblast
responsiveness to TGF-beta1 was assessed by examining smad phosphorylation,
smad binding element (SBE) promoter activity, connective tissue growth factor
(CTGF) expression and ability to contract collagen. RESULTS: Crohn's stricture
fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin
relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts
treated with siRNA directed against endoglin exhibited enhanced
TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells
transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting
SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from
strictures in CD express increased constitutive endoglin. Endoglin is a negative
regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3
phosphorylation, SBE promoter activity, CTGF production and collagen contraction.
Endometriosis dan endoglin 2011.enl Page 8

Reference Type: Journal Article

Record Number: 40

Plasma soluble endoglin concentration in

pre-eclampsia is associated with an increased
impedance to flow in the maternal and fetal
Year: 2010

Author: T. Chaiworapongsa, R. Romero, J. P. Kusanovic, P. Mittal, S. K. Kim, F.

Gotsch, N. G. Than, S. Mazaki-Tovi, E. Vaisbuch, O. Erez, L. Yeo, S. S. Hassan
and Y. Sorokin

Journal: Ultrasound Obstet Gynecol

Volume: 35
Issue: 2
Pages: 155-62

OBJECTIVES: To examine the relationship between abnormalities in uterine (UtA)

and/or umbilical artery (UA) Doppler velocimetry and maternal plasma
concentrations of soluble endoglin (sEng) in patients with pre-eclampsia (PE).
METHODS: A cross-sectional study was conducted in 135 normal pregnant women
and 69 patients with PE. Patients with PE were subclassified into four groups: those
who had Doppler abnormalities in both the UtA and UA, patients who had Doppler
abnormalities in the UtA alone, those who had Doppler abnormalities in the UA
alone, and patients without Doppler abnormalities in either vessel. Plasma
concentrations of sEng were determined by enzyme-linked immunosorbent assay.
RESULTS: Among patients with PE, those with abnormal UtA and UA Doppler
velocimetry had the highest median plasma concentration of sEng compared with
any other group (P < 0.001, Kruskal-Wallis test). Women with PE with normal
Doppler velocimetry in both vessels had the lowest median plasma concentration of
sEng. There was a significant relationship between plasma concentrations of sEng
and mean UtA resistance index (Spearman Rho = 0.5, P < 0.001) as well as UA
pulsatility index (Spearman Rho = 0.4, P = 0.002). Multiple regression analysis
suggested that Doppler abnormalities in the UtA and UA as well as gestational age
at blood sampling contributed to plasma sEng concentrations (P < 0.001).
CONCLUSIONS: Abnormalities of impedance to blood flow in the UtA and UA are
associated with an excess of sEng in the circulation of mothers with PE. These
findings suggest that the 'antiangiogenic state' in PE is partially reflected in
abnormalities of Doppler velocimetry.

Reference Type: Journal Article

Record Number: 15
Endometriosis dan endoglin 2011.enl Page 9

Serum endoglin levels in patients suffering from

systemic sclerosis and elevated systolic pulmonary
arterial pressure
Year: 2010

Author: P. X. Coral-Alvarado, M. F. Garces, J. E. Caminos, A. Iglesias-Gamarra, J.

F. Restrepo and G. Quintana

Journal: Int J Rheumatol

Volume: 2010

Background. Pulmonary arterial hypertension (PAH) is the main cause of

morbimortality in systemic sclerosis (SSc). Increased Eng expression has been
demonstrated in SSc patients. Objective. Ascertaining serum levels of Eng in SSc
patients with and without elevated systolic pulmonary arterial pressure (sPAP) and
comparing them with that of healthy volunteers. Methods. A cross-sectional study
was carried out. A commercial ELISA kit was used for measuring serum
concentrations of Eng in 60 subjects: 40 patients with SSc with and without elevated
sPAP, compared to 20 healthy control subjects. Elevated sPAP was detected by
echocardiogram. Results. No association between positive Eng and elevated sPAP
was found when compared to the SSc without elevated sPAP group (OR = 2.85;
0.65-12.88 95% CI; P = .11); however, an association was found between positive
Eng and elevated sPAP compared to healthy controls (OR = 23.22; 2.46-1050.33
95% CI; P = .001), and weak association was found between the positive Eng with
SSc without elevated sPAP group compared to healthy controls (OR = 8.14,
0.8-393.74 95% CI; P = .046). Conclusion. Raised serum levels of Eng in SSc
patients compared to healthy controls were found, suggesting a role for Eng in SSc
vasculopathy and not just in elevated sPAP. However, prospective studies are
needed to verify such observations.

Reference Type: Journal Article

Record Number: 48

Vascular endothelial growth factor and endoglin

expression in colorectal cancer
Year: 2010

Author: K. Dassoulas, M. Gazouli, G. Theodoropoulos, Z. Christoni, S. Rizos, A.

Zisi-Serbetzoglou, C. Glava, T. Karantanos, C. Klonaris and P. Karakitsos

Journal: J Cancer Res Clin Oncol

Volume: 136
Endometriosis dan endoglin 2011.enl Page 10

Issue: 5
Pages: 703-8

PURPOSE AND METHODS: Vascular endothelial growth factor (VEGF)

overexpression has been associated with advanced stage and poor survival in
several cancers. Additionally, endoglin was proposed as a marker of
neovascularization in solid malignancies. The aim of this study was to evaluate the
association between the VEGF and endoglin expression in colorectal carcinoma
patients, as well as to correlate the VEGF and endoglin expression with standard
parameters, to define their potential prognostic role. VEGF and endoglin expression
were evaluated in 99 unrelated patients with colorectal cancer using
immunohistochemistry. RESULTS: Vascular endothelial growth factor and
endoglobin expression were positively interrelated. No significant correlation of
VEGF and endoglin expression with clinicopathological parameters was observed in
our cases. The Kaplan-Meier survival curves have demonstrated a clear association
of cancer-specific overall survival with high VEGF, as well as high endoglin
expression. CONCLUSION: Our results support that VEGF and endoglin act as two
valuable indicators of prognosis.

Reference Type: Journal Article

Record Number: 8

CD105 (Endoglin) expression in breast carcinoma

effusions is a marker of poor survival
Year: 2010

Author: B. Davidson, H. T. Stavnes, M. Forsund, A. Berner and A. C. Staff

Journal: Breast
Volume: 19
Issue: 6
Pages: 493-8

We analyzed the expression and clinical role of endoglin (CD105) in breast

carcinoma effusions. Endoglin levels were measured in 36 effusion supernatants by
ELISA and studied for association with the cancer-associated markers calprotectin,
VEGF, and the VEGF receptor sFlt1. Endoglin expression was further studied in 46
effusions and 22 primary carcinomas using immunohistochemistry. The four
secreted molecules were detected in all specimens and their levels significantly
correlated (p < 0.001). In effusions, endoglin was localized to carcinoma cells and
reactive mesothelium using immunohistochemistry. Tumor cell expression was
higher in effusions compared to primary carcinomas (p = 0.025), and in
post-chemotherapy compared to pre-chemotherapy effusions (p = 0.017). Higher
tumor endoglin expression was associated with poor overall (p = 0.021) and
disease-free (p = 0.032) survival in univariate analysis, and was an independent
predictor in Cox multivariate analysis (p = 0.001 and p = 0.038, respectively). Our
Endometriosis dan endoglin 2011.enl Page 11

data suggest that endoglin may be an important therapeutic target in metastatic

breast cancer.

Reference Type: Journal Article

Record Number: 49

Endoglin as a marker in cervical paragangliomas

Year: 2010

Author: N. Eleno, A. Duwel, A. Munoz, J. Paz-Bouza, J. M. Lopez-Novoa and F.


Journal: Head Neck

Volume: 32
Issue: 6
Pages: 737-43

BACKGROUND: Endoglin is expressed on endothelium and is implicated in the

control of angiogenesis. This study compares the expression of endoglin with
vascular endothelial growth factor (VEGF), commonly used as a marker for
neoangiogenesis in cervical paragangliomas (CPG). METHODS: The CPG were
surgically obtained from 5 patients and compared with nontumoral lung obtained
from patients subjected to pulmonary resection. Detection with specific antibodies
was used to determine the expression of the proteins VEGF and endoglin. The
expressions of hypoxia-inducible factor (HIF) and vascular cell adhesion molecule-1
(VCAM-1) were used to determine the degree of hypoxia and capillarization,
respectively. RESULTS: Endoglin is located at the plasma membrane of endothelial
cells. The relative expression of endoglin is significantly higher in CPG respect to
lung (p < .02), whereas that of VEGF is similar. CONCLUSION: Endoglin expression
in CPG is significantly superior to that of VEGF and correlates with tumor

Reference Type: Journal Article

Record Number: 34

Alterations of serum and placental endoglin in

Year: 2010

Author: M. Fang, Y. He, H. Li, M. Wu, X. Shi and H. Du

Journal: J Int Med Res

Endometriosis dan endoglin 2011.enl Page 12

Volume: 38
Issue: 1
Pages: 43-51

Serum levels of endoglin were measured in pre-eclamptic women in their third

trimester and in women in their second trimester who later developed
pre-eclampsia. Placental levels of endoglin at birth were also determined in
pre-eclamptic women and healthy controls. Serum endoglin was significantly higher
in pre-eclamptic women in the third trimester than in controls (median 35.15 versus
10.35 ng/ml, respectively) and in women with severe compared with mild
pre-eclampsia (median 51.68 versus 20.99 ng/ml, respectively). Placental endoglin
was also significantly higher in pre-eclamptic women than controls (median 26.24
versus 9.21 ng/mg, respectively) and in women with severe compared with mild
pre-eclampsia (median 28.77 versus 13.38 ng/mg, respectively). Pregnant women
in the second trimester who eventually developed pre-eclampsia had significantly
higher serum endoglin than age- and gestational age-matched controls (median
5.90 versus 5.20 ng/ml, respectively). These findings suggest that endoglin plays an
important role in the pathogenesis of pre-eclampsia.

Reference Type: Journal Article

Record Number: 19

Endoglin differentially regulates TGF-beta-induced

Smad2/3 and Smad1/5 signalling and its expression
correlates with extracellular matrix production and
cellular differentiation state in human chondrocytes
Year: 2010

Author: K. W. Finnson, W. L. Parker, Y. Chi, C. D. Hoemann, M. B. Goldring, J.

Antoniou and A. Philip

Journal: Osteoarthritis Cartilage

Volume: 18
Issue: 11
Pages: 1518-27

OBJECTIVE: Transforming growth factor-beta (TGF-beta) plays a critical role in

cartilage homeostasis and deregulation of its signalling is implicated in osteoarthritis
(OA). TGF-beta isoforms signal through a pair of transmembrane serine/threonine
kinases known as the type I and type II TGF-beta receptors. Endoglin is a TGF-beta
co-receptor that binds TGF-beta with high affinity in the presence of the type II
TGF-beta receptor. We have previously shown that endoglin is expressed in human
chondrocytes and that it forms a complex with the TGF-beta signalling receptors.
However, the functional significance of endoglin expression in chondrocytes is
unknown. Our objective was to determine whether endoglin regulates TGF-beta
Endometriosis dan endoglin 2011.enl Page 13

Smad signalling and extracellular matrix (ECM) production in human chondrocytes

and whether its expression varies with chondrocyte differentiation state. METHOD:
Endoglin function was determined by overexpression or antisense morpholino
siRNA knockdown of endoglin in human chondrocytes and measuring
TGF-beta-induced Smad phosphorylation, transcriptional activity and ECM
production. Alterations in endoglin expression levels were determined during
subculture-induced dedifferentiation of human chondrocytes and in normal vs OA
cartilage samples. RESULTS: Endoglin enhances TGF-beta1-induced Smad1/5
phosphorylation and inhibits TGF-beta1-induced Smad2 phosphorylation,
Smad3-driven transcriptional activity and ECM production in human chondrocytes.
In addition, the enhancing effect of endoglin siRNA knockdown on
TGF-beta1-induced Smad3-driven transcription is reversed by ALK1
overexpression. Furthermore, endoglin levels are increased in chondrocytes
following subculture-induced dedifferentiation and in OA cartilage as compared to
normal cartilage. CONCLUSION: Together, our results suggest that endoglin
regulates the balance between TGF-beta/ALK1/Smad1/5 and ALK5/Smad2/3
signalling and ECM production in human chondrocytes and that endoglin may
represent a marker for chondrocyte phenotype.

Reference Type: Journal Article

Record Number: 37

Maternal plasma soluble endoglin at 11-13 weeks'

gestation in pre-eclampsia
Year: 2010

Author: J. M. Foidart, C. Munaut, F. Chantraine, R. Akolekar and K. H. Nicolaides

Journal: Ultrasound Obstet Gynecol

Volume: 35
Issue: 6
Pages: 680-7

OBJECTIVES: To examine the performance of screening for pre-eclampsia (PE) by

a combination of maternal factors, soluble endoglin (sEng), pregnancy associated
plasma protein-A (PAPP-A), placental growth factor (PlGF) and uterine artery lowest
pulsatility index (L-PI) at 11-13 weeks' gestation. METHODS: Uterine artery L-PI,
sEng, PAPP-A and PlGF were measured at 11-13 weeks in 90 singleton
pregnancies that subsequently developed PE, including 30 that required delivery
before 34 weeks (early PE) and 60 with late PE, and 180 unaffected controls.
Screening performance for PE by maternal factors, sEng, PAPP-A, PlGF and
uterine artery L-PI and their combinations was determined. RESULTS: In early PE,
compared to controls, plasma sEng and uterine L-PI were significantly increased
and serum PAPP-A and PlGF were decreased. In late PE, compared to controls,
serum PlGF was decreased and uterine L-PI was increased but plasma sEng and
serum PAPP-A were not significantly different. In screening for early PE, the
Endometriosis dan endoglin 2011.enl Page 14

detection rate for a 10% false-positive rate was 46.7% for sEng alone and 96.3% for
a combination of maternal factors, sEng, PlGF and uterine artery L-PI.
CONCLUSIONS: Effective screening for early PE can be provided by a combination
of maternal factors, sEng, PlGF and uterine artery L-PI at 11-13 weeks' gestation.

Reference Type: Journal Article

Record Number: 50

Targeting cancer vasculature via endoglin/CD105: a

novel antibody-based diagnostic and therapeutic
strategy in solid tumours
Year: 2010

Author: E. Fonsatti, H. J. Nicolay, M. Altomonte, A. Covre and M. Maio

Journal: Cardiovasc Res

Volume: 86
Issue: 1
Pages: 12-9

Endoglin/CD105 is well acknowledged as being the most reliable marker of

proliferation of endothelial cells, and it is overexpressed on tumour neovasculature.
Our current knowledge of its structure, physiological role, and tissue distribution
suggests that targeting of endoglin/CD105 is a novel and powerful diagnostic and
therapeutic strategy in human malignancies, through the imaging of
tumour-associated angiogenesis and the inhibition of endothelial cell functions
related to tumour angiogenesis. Among biotherapeutic agents, monoclonal
antibodies have shown a major impact on the clinical course of human malignancies
of different histotypes. Along this line, the potential efficacy of anti-endoglin/CD105
antibodies and their derivatives for clinical purposes in cancer is supported by a
large body of available pre-clinical in vitro and in vivo data. In this review, the main
findings supporting the translation of antibody-based endoglin/CD105 targeting from
pre-clinical studies to clinical applications in human cancer are summarized and

Reference Type: Journal Article

Record Number: 23

VEGF Induces More Severe Cerebrovascular

Dysplasia in Endoglin than in Alk1 Mice
Year: 2010
Endometriosis dan endoglin 2011.enl Page 15

Author: Q. Hao, Y. Zhu, H. Su, F. Shen, G. Y. Yang, H. Kim and W. L. Young

Journal: Transl Stroke Res

Volume: 1
Issue: 3
Pages: 197-201

Brain arteriovenous malformations (BAVMs) are an important cause of intracranial

hemorrhage (ICH) in young adults. A small percent of BAVMs is due to hereditary
hemorrhagic telangiectasia 1 and 2 (HHT1 and 2), which are caused by mutations in
two genes involved in TGF-beta signaling: endoglin (ENG) and activin-like kinase 1
(ALK1). The BAVM phenotype is an incomplete penetrant in HHT patients, and the
mechanism is unknown. We tested the hypothesis that a "response-to-injury"
triggers abnormal vascular (dysplasia) development, using Eng and Alk1
haploinsufficient mice. Adeno-associated virus (AAV) expressing vascular
endothelial growth factor (VEGF) was used to mimic the injury conditions. VEGF
overexpression caused a similar degree of angiogenesis in the brain of all groups,
except that the cortex of Alk1(+/-) mice had a 33% higher capillary density than
other groups. There were different levels of cerebrovascular dysplasia in
haploinsufficient mice (Eng(+/)>Alk1(+/-)), which simulates the relative penetrance
of BAVM in HHT patients (HHT1>HHT2). Few dysplastic capillaries were observed
in AAV-LacZ-injected mice. Our data indicate that both angiogenic stimulation and
genetic alteration are necessary for the development of dysplasia, suggesting that
anti-angiogenic therapies might be adapted to slow the progression of the disease
and decrease the risk of spontaneous ICH.

Reference Type: Journal Article

Record Number: 31

Matrix metalloproteinase-14 (MT1-MMP)-mediated

endoglin shedding inhibits tumor angiogenesis
Year: 2010

Author: L. J. Hawinkels, P. Kuiper, E. Wiercinska, H. W. Verspaget, Z. Liu, E.

Pardali, C. F. Sier and P. ten Dijke

Journal: Cancer Res

Volume: 70
Issue: 10
Pages: 4141-50

Endoglin is a transforming growth factor-beta coreceptor with a crucial role in

angiogenesis. A soluble form of endoglin is present in the circulation, but the role of
soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding
Endometriosis dan endoglin 2011.enl Page 16

mechanism is not known. Therefore, we examined the role of sEndoglin in tumor

angiogenesis and the mechanism by which the extracellular domain of endoglin is
released from the membrane.In colorectal cancer specimens, we observed high
endothelial endoglin protein expression, accompanied with slightly lower sEndoglin
levels in the circulation, compared with healthy controls. In vitro analysis using
endothelial sprouting assays revealed that sEndoglin reduced spontaneous and
vascular endothelial growth factor-induced endothelial sprouting. Human umbilical
vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin
shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14
short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease.
Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in
sEndoglin levels. Endoglin shedding required a direct interaction between endoglin
and membrane-localized MMP-14. Using cleavage site mutants, we determined that
MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain.
Taken together, this study shows that MMP-14 mediates endoglin shedding, which
may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor

Reference Type: Journal Article

Record Number: 27

Transforming growth factor-beta co-receptor

endoglin suppresses breast cancer invasion and
Year: 2010

Author: L. Henry, D. Johnson, S. Lee, P. Quinlan, T. Crook, A. Thompson, J.

Reis-Filho and C. Isacke

Journal: Breast Cancer Res

Volume: 12 Suppl 1
Pages: O6

Reference Type: Journal Article

Record Number: 10

Endoglin expression in breast tumor cells

suppresses invasion and metastasis and correlates
with improved clinical outcome
Endometriosis dan endoglin 2011.enl Page 17

Year: 2010

Author: L. A. Henry, D. A. Johnson, D. Sarrio, S. Lee, P. R. Quinlan, T. Crook, A.

M. Thompson, J. S. Reis-Filho and C. M. Isacke

Journal: Oncogene

Tumor growth factor-beta (TGF-beta) signaling in cancer has been implicated in

growth suppression of early lesions and enhancing tumor cell invasion and
metastasis. However, the cellular mechanisms that determine this signaling output
in individual tumors are still largely unknown. In endothelial cells, TGF-beta signaling
is modulated by the TGF-beta co-receptor endoglin (CD105). Here we demonstrate
that endoglin is expressed in a subset of invasive breast cancers and cell lines and
is subject to epigenetic silencing by gene methylation. Endoglin downregulation in
non-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3D
culture, but does not promote cell migration or transformation. In contrast, in the
presence of activated ErbB2, endoglin downregulation in MCF10A cells leads to
enhanced invasion into a 3D matrix. Consistent with these data, ectopic expression
of endoglin in MDA-MB-231 cells blocks TGF-beta-enhanced cell motility and
invasion and reduces lung colonization in an in vivo metastasis model. Unlike
endothelial cells, endoglin does not modulate Smad-mediated TGF-beta signaling in
breast cells but attenuates the cytoskeletal remodeling to impair cell migration and
invasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglin
expression in the tumor cell compartment correlates with ENG gene methylation and
poor clinical outcome.Oncogene advance online publication, 1 November 2010;

Reference Type: Journal Article

Record Number: 30

Soluble endoglin in preeclamptic patients with or

without HELLP syndrome
Year: 2010

Author: A. Hertig, J. Fort, G. Lefevre, N. Chabbert-Buffet, M. Uzan, E. Rondeau

and P. Rozenberg

Journal: Am J Obstet Gynecol

Volume: 202
Issue: 6
Pages: 594 e1-4

OBJECTIVE: The pathogenesis of the HELLP (hemolysis, enzyme liver, low

platelets) syndrome is unknown. Recently soluble endoglin (sEng) was identified as
a cause of the appearance of schistocytes and liver pathology in an animal model of
preeclampsia (PE). STUDY DESIGN: We explored the value of sEng in 82 women
Endometriosis dan endoglin 2011.enl Page 18

who delivered in a context of normal pregnancy (NP, n = 10), PE (n = 49), or HELLP

(n = 23). RESULTS: sEng was elevated in pathological pregnancies (66.7 +/- 62
and 75.7 +/- 48 pg/mL in PE and HELLP, respectively, vs 5.29 +/- 1.25 in NP, P <
.001 for both comparisons) and was correlated with an increase in transaminases
(r(2) = 0.17; P = .05), but it was not statistically different between PE and HELLP.
CONCLUSION: Although recent literature findings demonstrated a role of sEng in
the pathophysiology of HELLP syndrome in animal models, we found that, at the
time of delivery, sEng was not specifically elevated in preeclamptic patients with

Reference Type: Journal Article

Record Number: 47

Endoglin is involved in BMP-2-induced osteogenic

differentiation of periodontal ligament cells through
a pathway independent of Smad-1/5/8
Year: 2010

Author: O. Ishibashi, M. Ikegame, F. Takizawa, T. Yoshizawa, M. A. Moksed, F.

Iizawa, H. Mera, A. Matsuda and H. Kawashima

Journal: J Cell Physiol

Volume: 222
Issue: 2
Pages: 465-73

The periodontal ligament (PDL), a connective tissue located between the cementum
of teeth and the alveolar bone of mandibula, plays a crucial role in the maintenance
and regeneration of periodontal tissues. The PDL contains fibroblastic cells of a
heterogeneous cell population, from which we have established several cell lines
previously. To analyze characteristics unique for PDL at a molecular level, we
performed cDNA microarray analysis of the PDL cells versus MC3T3-E1
osteoblastic cells. The analysis followed by validation by reverse
transcription-polymerase chain reaction and immunochemical staining revealed that
endoglin, which had been shown to associate with transforming growth factor
(TGF)-beta and bone morphogenetic proteins (BMPs) as signaling modulators, was
abundantly expressed in PDL cells but absent in osteoblastic cells. The knockdown
of endoglin greatly suppressed the BMP-2-induced osteoblastic differentiation of
PDL cells and subsequent mineralization. Interestingly, the endoglin knockdown did
not alter the level of Smad-1/5/8 phosphorylation induced by BMP-2, while it
suppressed the BMP-2-induced expression of Id1, a representative BMP-responsive
gene. Therefore, it is conceivable that endoglin regulates the expression of
BMP-2-responsive genes in PDL cells at some site downstream of Smad-1/5/8
phosphorylation. Alternatively, we found that Smad-2 as well as Smad-1/5/8 was
Endometriosis dan endoglin 2011.enl Page 19

phosphorylated by BMP-2 in the PDL cells, and that the BMP-2-induced Smad-2
phosphorylation was suppressed by the endoglin knockdown. These results, taken
together, raise a possibility that PDL cells respond to BMP-2 via a unique signaling
pathway dependent on endoglin, which is involved in the osteoblastic differentiation
and mineralization of the cells.

Reference Type: Journal Article

Record Number: 17

Dextran sulfate sodium leads to chronic colitis and

pathological angiogenesis in Endoglin
heterozygous mice
Year: 2010

Author: M. Jerkic, M. Peter, D. Ardelean, M. Fine, M. A. Konerding and M. Letarte

Journal: Inflamm Bowel Dis

Volume: 16
Issue: 11
Pages: 1859-70

BACKGROUND: Pathological angiogenesis is an intrinsic component of chronic

intestinal inflammation, which results in remodeling and expansion of the gut
microvascular bed. Endoglin is essential for endothelial cell function and
physiological angiogenesis. In this study we investigated its potential role in the
regulation of inflammation by testing the response of Endoglin heterozygous (Eng(+
-)) mice to experimental colitis. METHODS: C57BL/6 Eng(+/-) and littermate control
mice drank water supplemented with 3% dextran sulfate sodium (DSS) for 5 days
and were monitored for up to 26 days for clinical signs of colitis. Inflammation, crypt
damage, and angiogenic index were scored on histological sections of distal colon.
Levels of the vascular endothelial growth factor (VEGF) and angiopoietins were
measured by real-time polymerase chain reaction, enzyme-linked immunosorbent
assay, and/or Western blots. Vascular permeability was assessed using Evans
Blue. RESULTS: Eng(+/-) and control mice developed acute colitis, which peaked at
day 9. While control mice recovered by days 19-26, Eng(+/-) mice progressed to
chronic colitis and showed numerous vascular protrusions penetrating into the
serosa of the inflamed distal colon. Prior to DSS induction, VEGF levels and
vascular permeability were higher in the distal colon of Eng(+/-) mice, while
angiopoietin 1 and 2 levels were unchanged. In the chronic phase of colitis, VEGF
levels were increased in both groups of mice and remained significantly higher in
the Eng(+/-) mice. CONCLUSIONS: Higher VEGF levels and increased vascular
permeability in the distal colon may predispose Eng(+/-) mice to progress to chronic
and persistent bowel inflammation, associated with pathological angiogenesis.
Endometriosis dan endoglin 2011.enl Page 20

Reference Type: Journal Article

Record Number: 7

Transforming growth factor Beta and soluble

endoglin in the healthy senior and in Alzheimer ' s
disease patients
Year: 2010

Author: B. Juraskova, C. Andrys, I. Holmerova, D. Solichova, D. Hrnciarikova, H.

Vankova, T. Vasatko and J. Krejsek

Journal: J Nutr Health Aging

Volume: 14
Issue: 9
Pages: 758-61

OBJECTIVES: Senescence of the immune system and of endothelial cells can

contribute to age-dependent vascular and neurodegenerative disorders including
Alzheimer's disease. The aim of this study is an assessment of putative
relationships of serum levels of transforming growth factor beta (TGFbeta) and
soluble endoglin (sCD105) and neurodegeneration, and of changes of these
molecules in the course of ageing. DESIGN: The subjects of the study consisted of
three groups, the first one was 63 otherwise healthy middle - aged participants, 31
females, 32 males, of average age 35 years. The second group was formed by 58
healthy, self-dependent inhabitants of nursing homes, 44 females and 14 males,
average age 83.5 years. The third group comprised of 129 Alzheimer's disease
patients, 86 females, 43 males, of average age 80 years, with MMSE score that
ranged from 16 to 20. MEASUREMENT: Serum levels of TGF beta and soluble
endoglin were measured by the ELISA method in samples of peripheral blood using
commercial kits. RESULTS: The serum level of TGFbeta was 34,339 +/- 6,420 pg
ml in the healthy younger group, 37,555 +/- 11,944 pg/ml in the healthy seniors, and
29,057 +/- 11,455 pg/ml in Alzheimer's disease patients. Compared to healthy
seniors, the serum level of TGFbeta was significantly decreased in Alzheimer's
disease patients (p < 0.01). The serum level of endoglin were 4.88 +/- 0.95 mug/ml
in the healthy younger group; 6.11 +/- 1.38 mug/ml in healthy seniors, and 7.20 +/-
1.72 mug/ml in patients with Alzheimer's disease, respectively. The serum level of
endoglin was significantly higher (p < 0.001) in senescent healthy persons
compared to the younger control group. When compared with healthy seniors,
patients with Alzheimer's disease had significantly elevated (p < 0.001) serum level
of endoglin. CONCLUSIONS: Decreased levels of TGF beta in Alzheimer's disease
may result in impairment of cerebral circulation reflected in the increased endoglin
levels. These findings may indicate involvement of the immune system in Alzheimer
rsquor; s disease pathogenesis.
Endometriosis dan endoglin 2011.enl Page 21

Reference Type: Journal Article

Record Number: 6

Usefulness of soluble endoglin as a noninvasive

measure of left ventricular filling pressure in heart
Year: 2010

Author: N. K. Kapur, K. S. Heffernan, A. A. Yunis, P. Parpos, M. S. Kiernan, N. A.

Sahasrabudhe, C. D. Kimmelstiel, D. A. Kass, R. H. Karas and M. E. Mendelsohn

Journal: Am J Cardiol
Volume: 106
Issue: 12
Pages: 1770-6

Progressive left ventricular (LV) dysfunction induces expression of the cytokine

transforming growth factor-beta1. Endoglin (CD105) is a transforming growth
factor-beta1 co-receptor that is released into the circulation as soluble endoglin
(sEng). The objective of the present study was to assess the serum levels of sEng
in patients with heart failure and to identify the predictive value of sEng for detecting
elevated left ventricular end-diastolic pressures (LVEDPs). We measured the sEng
levels in 82 consecutive patients with suspected LV dysfunction referred for
determination of left heart filling pressures using cardiac catheterization. Among
these subjects, the sEng levels correlated with the LVEDP (R = 0.689; p <0.0001),
irrespective of the LV ejection fraction. Using a receiving operating characteristic
curve, the sEng levels predicted an LVEDP of >/=16 mm Hg with an area under the
curve of 0.85, exceeding the measured area under the curves for both atrial and
brain natriuretic peptide, currently used biomarkers for heart failure diagnosis (atrial
natriuretic peptide 0.68 and brain natriuretic peptide 0.65; p <0.01 vs sEng). In 10
subjects receiving medical therapy guided by invasive hemodynamic monitoring for
heart failure, decreased a pulmonary capillary wedge pressure was associated with
a reduced sEng level (R = 0.75, p = 0.008). Finally, compared to 25 healthy
controls, the sEng levels were elevated in subjects with suspected LV dysfunction
(3,589 +/- 588 vs 4,257 +/- 966 pg/ml, respectively, p <0.005) and correlated directly
with the New York Heart Association class (R = 0.501, p<0.001). In conclusion,
circulating levels of sEng are elevated in patients with increased LVEDP and New
York Heart Association class, irrespective of the LV ejection fraction. sEng levels
also decreased in association with a reduced cardiac filling pressure after diuresis.
These findings have identified circulating sEng as a sensitive measure of elevated
left heart filling pressures.

Reference Type: Journal Article

Record Number: 33
Endometriosis dan endoglin 2011.enl Page 22

The effect of nicotine on the production of soluble

fms-like tyrosine kinase-1 and soluble endoglin in
human umbilical vein endothelial cells and
Year: 2010

Author: J. Y. Kwon, S. W. Bai, Y. G. Kwon, S. H. Kim, C. H. Kim, M. H. Kang, J. A.

Linton and Y. W. Park

Journal: Acta Obstet Gynecol Scand

Volume: 89
Issue: 4
Pages: 565-71

OBJECTIVES: To evaluate the effect of nicotine on the production of soluble

fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) in human umbilical
vein endothelial cells (HUVECs) and trophoblast cells, and to assess the
involvement of alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) in this
process. METHODS: Commercially available full-term placental trophoblasts and
HUVECs derived from the umbilical cord of a normal pregnancy were used. The
expression of alpha7 nAChR was assessed by immunostaining, RT-PCR, and
western blotting. The expression of sFlt-1 and sEng protein in the cell media after 6
and 24 hours of treatment with nicotine was evaluated using a commercially
available ELISA. To determine the involvement of alpha7 nAChR in the nicotinic
effect, cells were treated with the alpha7 nAChR antagonist alpha-bungarotoxin
(alpha-BGT) prior to the nicotine exposure. Levels of significance were determined
using the Student's t-test and one-way ANOVA, and a p-value < 0.05 was
considered significant. MAIN OUTCOME MEASURES: The levels of sFlt-1 and
sEng protein were evaluated before and after the nicotine treatment with or without
alpha-BGT pre-treatment. RESULTS: In trophoblast cells, a significant reduction of
sFlt-1 and sEng protein was observed after 24 hours of nicotine treatment as
compared to the untreated group (p = 0.002, 0.000). In HUVECs, nicotine only had
a suppressive effect on the expression of sEng at 6 hours (p = 0.03); there was no
effect on sFlt-1 expression. However, pre-treatment with alpha-BGT did not reverse
the nicotine-induced suppressive effect on the expression of sFlt-1 and sEng in
trophoblasts and HUVECs. CONCLUSIONS: Nicotine reduced the production of
sFlt-1 and sEng in trophoblasts and sEng in HUVECs. This effect was not mediated
by alpha7 nAChR.

Reference Type: Journal Article

Record Number: 11

Endoglin suppresses human prostate cancer

Endometriosis dan endoglin 2011.enl Page 23

Year: 2011

Author: M. Lakshman, X. Huang, V. Ananthanarayanan, B. Jovanovic, Y. Liu, C. S.

Craft, D. Romero, C. P. Vary and R. C. Bergan

Journal: Clin Exp Metastasis

Volume: 28
Issue: 1
Pages: 39-53

Endoglin is a transmembrane receptor that suppresses human prostate cancer

(PCa) cell invasion. Small molecule therapeutics now being tested in humans can
activate endoglin signaling. It is not known whether endoglin can regulate metastatic
behavior, PCa tumor growth, nor what signaling pathways are linked to these
processes. This study sought to investigate the effect of endoglin on these
parameters. We used a murine orthotopic model of human PCa metastasis,
designed by us to measure effects at early steps in the metastatic cascade, and
implanted PCa cells stably engineered to express differing levels of endoglin. We
now extend this model to measure cancer cells circulating in the blood. Progressive
endoglin loss led to progressive increases in the number of circulating PCa cells as
well as to the formation of soft tissue metastases. Endoglin was known to suppress
invasion by activating the Smad1 transcription factor. We now show that it
selectively activates specific Smad1-responsive genes, including JUNB, STAT1, and
SOX4. Increased tumor growth and increased Ki67 expression in tissue was seen
only with complete endoglin loss. By showing that endoglin increased
TGFbeta-mediated suppression of cell growth in vitro and TGFbeta-mediated
signaling in tumor tissue, loss of this growth-suppressive pathway appears to be
implicated at least in part for the increased size of endoglin-deficient tumors.
Endoglin is shown for the first time to suppress cell movement out of primary tumor
as well as the formation of distant metastasis. It is also shown to co-regulate tumor
growth and metastatic behavior in human PCa.

Reference Type: Journal Article

Record Number: 22

The physiological role of endoglin in the

cardiovascular system
Year: 2010

Author: J. M. Lopez-Novoa and C. Bernabeu

Journal: Am J Physiol Heart Circ Physiol

Volume: 299
Issue: 4
Endometriosis dan endoglin 2011.enl Page 24

Pages: H959-74

Endoglin (CD105) is an integral membrane glycoprotein that serves as a coreceptor

for members of the transforming growth factor-beta superfamily of proteins. A major
role for endoglin in regulating transforming growth factor-beta-dependent vascular
remodeling and angiogenesis has been postulated based on the following: 1)
endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1, a
disease characterized by vascular malformations; 2) endoglin knockout mice die at
midgestation because of defective angiogenesis; 3) endoglin is overexpressed in
neoangiogenic vessels, during inflammation, and in solid tumors; and 4) endoglin
regulates the expression and activity of endothelial nitric oxide synthase, which is
involved in angiogenesis and vascular tone. Besides the predominant form of the
endoglin receptor (long endoglin isoform), two additional forms of endoglin have
been recently reported to play a role in the vascular pathology and homeostasis: the
alternatively spliced short endoglin isoform and a soluble endoglin form that is
proteolytically cleaved from membrane-bound endoglin. The purpose of this review
is to underline the role that the different forms of endoglin play in regulating
angiogenesis, vascular remodeling, and vascular tone, as well as to analyze the
molecular and cellular mechanisms supporting these effects.

Reference Type: Journal Article

Record Number: 35

Pathogenesis of arteriovenous malformations in the

absence of endoglin
Year: 2010

Author: M. Mahmoud, K. R. Allinson, Z. Zhai, R. Oakenfull, P. Ghandi, R. H.

Adams, M. Fruttiger and H. M. Arthur

Journal: Circ Res

Volume: 106
Issue: 8
Pages: 1425-33

RATIONALE: Arteriovenous malformations (AVMs) result in anomalous direct blood

flow between arteries and veins, bypassing the normal capillary bed. Depending on
size and location, AVMs may lead to severe clinical effects including systemic
cyanosis (pulmonary AVMs), hemorrhagic stroke (cerebral AVMs) and high output
cardiac failure (hepatic AVMs). The factors leading to AVM formation are poorly
understood, but patients with the familial disease hereditary hemorrhagic
telangiectasia (HHT) develop AVMs at high frequency. As most HHT patients have
mutations in ENG (endoglin) or ACVRL1 (activin receptor-like kinase 1), a better
understanding of the role of these genes in vascular development is likely to reveal
the etiology of AVM formation. OBJECTIVE: Using a mouse with a conditional
mutation in the Eng gene, we investigated the sequence of abnormal cellular events
Endometriosis dan endoglin 2011.enl Page 25

occurring during development of an AVM. METHODS AND RESULTS: In the

absence of endoglin, subcutaneous Matrigel implants in adult mice were populated
by reduced numbers of new blood vessels compared with controls, and resulted in
local venous enlargement (venomegaly). To investigate abnormal vascular
responses in more detail, we turned to the more readily accessible vasculature of
the neonatal retina. Endoglin-deficient retinas exhibited delayed remodeling of the
capillary plexus, increased proliferation of endothelial cells and localized AVMs.
Muscularization of the resulting arteriovenous shunts appeared to be a secondary
response to increased blood flow. CONCLUSIONS: AVMs develop when an
angiogenic stimulus is combined with endoglin depletion. Moreover, AVM formation
appears to result from the combination of delayed vascular remodeling and an
inappropriate endothelial cell proliferation response in the absence of endoglin.

Reference Type: Journal Article

Record Number: 21

Soluble endoglin for the prediction of preeclampsia

in a high risk cohort
Year: 2010

Author: S. E. Maynard, T. A. Moore Simas, L. Bur, S. L. Crawford, M. J. Solitro and

B. A. Meyer

Journal: Hypertens Pregnancy

Volume: 29
Issue: 3
Pages: 330-41

OBJECTIVES: To evaluate soluble endoglin (sEng) and the soluble fms-like tyrosine
kinase 1 (sFlt1) to placental growth factor (PlGF) ratio for the prediction of
preeclampsia in high-risk women, and to evaluate differences in sEng between
women with high-risk singleton and multiple gestation pregnancies. STUDY
DESIGN: We collected serial serum specimens from 119 women at high
preeclampsia risk. sEng, sFlt1 and PlGF were measured by ELISA. RESULTS:
Among subjects who did not develop preeclampsia, mean serum sEng was
significantly higher in those with multiple gestation pregnancies vs. high-risk
singletons. Among women with singleton gestations, mean serum sEng was higher
in subjects who developed early-onset (<34 weeks) and late-onset (>or= 34 weeks)
preeclampsia, as compared with subjects without preeclampsia, from 22 weeks and
28 weeks gestation onward, respectively. The within-woman rate of change of sEng
was also higher in women who later developed preeclampsia. CONCLUSIONS:
sEng is higher in women with multiple gestations vs. high-risk singleton
pregnancies. In high-risk women, serum sEng is increased prior to preeclampsia
Endometriosis dan endoglin 2011.enl Page 26

Reference Type: Journal Article

Record Number: 5

Expression and functional analysis of endoglin in

isolated liver cells and its involvement in fibrogenic
Smad signalling
Year: 2011

Author: S. K. Meurer, L. Tihaa, E. Borkham-Kamphorst and R. Weiskirchen

Journal: Cell Signal

Volume: 23
Issue: 4
Pages: 683-99

Endoglin is an accessory component of the TGF-beta-binding receptor complex that

differentially modulates TGF-beta and BMP responses. The existence of two splice
variants L- and S-endoglin which differ in their cytoplasmic domain has already been
shown in human and mice. Endoglin is located on the cell surfaces of cultured
hepatic stellate cells and transdifferentiated myofibroblasts suggesting that this
receptor might be associated with the profibrogenic attributes of these liver cell
subpopulations. We now show that endoglin expression is increased in
transdifferentiating hepatic stellate cells and in two models of liver fibrosis (i.e. bile
duct ligation and carbon tetrachloride model) and further detectable in cultured
portal fibroblasts representing another important fibrogenic cell type but not in
hepatocytes. In respect to TGF-beta1-signalling, we demonstrate that endoglin
interacts with and is phosphorylated by TbetaRII. In hepatic stellate cells,
TGF-beta1 upregulates endoglin expression most likely via the ALK5 pathway and
requires the SP1 transcription factor. We further identified a novel rat splice variant
that is structurally and functionally different from that identified in human and mouse.
Transient overexpression of endoglin resulted in a strong increase of
TGF-beta1-driven Smad1/5 phosphorylation and alpha-smooth muscle actin
expression in a hepatic stellate cell line. In supernatants of respective cultures, we
could detect the ectodomain of endoglin suggesting that shedding is a further key
process involved in the regulation of this surface receptor.

Reference Type: Journal Article

Record Number: 16

Critical role of endoglin in tumor cell plasticity of

Ewing sarcoma and melanoma
Year: 2011
Endometriosis dan endoglin 2011.enl Page 27

Author: E. Pardali, D. W. van der Schaft, E. Wiercinska, A. Gorter, P. C.

Hogendoorn, A. W. Griffioen and P. Ten Dijke

Journal: Oncogene
Volume: 30
Issue: 3
Pages: 334-45

Tumor cell plasticity enables certain types of highly malignant tumor cells to
dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which
enables them to 'adapt' during tumor progression and escape conventional
therapeutic strategies. This plastic phenotype of aggressive cancer cells enables
them to express endothelial cell-specific markers and form tube-like structures, a
phenotype that has been linked to aggressive behavior and poor prognosis. We
demonstrate here that the transforming growth factor (TGF)-beta co-receptor
endoglin, an endothelial cell marker, is expressed by tumor cells and its expression
correlates with tumor cell plasticity in two types of human cancer, Ewing sarcoma
and melanoma. Moreover, endoglin expression was significantly associated with
worse survival of Ewing sarcoma patients. Endoglin knockdown in tumor cells
interferes with tumor cell plasticity and reduces invasiveness and
anchorage-independent growth in vitro. Ewing sarcoma and melanoma cells with
reduced endoglin levels showed reduced tumor growth in vivo. Mechanistically, we
provide evidence that endoglin, while interfering with TGF-beta signaling, is required
for efficient bone morphogenetic protein, integrin, focal adhesion kinase and
phosphoinositide-3-kinase signaling in order to maintain tumor cell plasticity. The
present study delineates an important role of endoglin in tumor cell plasticity and
progression of aggressive tumors.

Reference Type: Journal Article

Record Number: 29

The effect of immune factors, tumor necrosis

factor-alpha, and agonistic autoantibodies to the
angiotensin II type I receptor on soluble fms-like
tyrosine-1 and soluble endoglin production in
response to hypertension during pregnancy
Year: 2010

Author: M. R. Parrish, S. R. Murphy, S. Rutland, K. Wallace, K. Wenzel, G.

Wallukat, S. Keiser, L. F. Ray, R. Dechend, J. N. Martin, J. P. Granger and B.

Journal: Am J Hypertens
Endometriosis dan endoglin 2011.enl Page 28

Volume: 23
Issue: 8
Pages: 911-6

BACKGROUND: Preeclampsia is considered a disease of immunological origin

associated with abnormalities in inflammatory cytokines, tumor necrosis factor-alpha
(TNF-alpha), and activated lymphocytes secreting autoantibodies to the angiotensin
II receptor (AT1-AA). Recent studies have also demonstrated that an imbalance of
angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1), and sEndoglin, exists in
preeclampsia; however, the mechanisms that initiate their overproduction are
unclear. METHODS: To determine the role of immune regulation of these factors,
circulating and placental sFlt-1 and/or sEndoglin was examined from pregnant rats
chronically treated with TNF-alpha or AT1-AA. On day 19 of gestation blood
pressure was analyzed and serum and tissues were collected. Placental villous
explants were excised and cultured on matrigel coated inserts for 24 h and sFlt-1
and sEndoglin was measured from media. RESULTS: In response to
TNF-alpha-induced hypertension, sFlt-1 increased from 180 +/- 5 to 2,907 +/- 412
pg/ml. sFlt-1 was also increased from cultured placental explants of TNF-alpha
induced hypertensive pregnant rats (n = 12) (2,544 +/- 1,132 pg/ml) vs. explants
from normal pregnant (NP) rats (n = 12) (2,189 +/- 586 pg/ml) where as sEng was
undetectable. Circulating sFlt-1 increased from 245 +/- 38 to 3,920 +/- 798 pg/ml in
response to AT1-AA induced hypertension. sFlt-1 levels were higher (3,400 +/- 350
vs. 2,480 +/- 900 pg/ml) in placental explants from AT1-AA infused rats (n = 12)
than NP rats (n = 7). In addition, sEndoglin increased from 30 +/- 2.7 to 44 +/- 3.3
pg/ml (P < 0.047) in AT1-AA infused rats but was undetectable in the media of the
placental explants. CONCLUSIONS: These data suggest that immune factors may
serve as an important stimulus for both sFlt-1 and sEndoglin production in response
to placental ischemia.

Reference Type: Journal Article

Record Number: 4

The role of the TGF-beta coreceptor endoglin in

Year: 2010

Author: E. Perez-Gomez, G. Del Castillo, S. Juan Francisco, J. M. Lopez-Novoa, C.

Bernabeu and M. Quintanilla

Journal: ScientificWorldJournal
Volume: 10
Pages: 2367-84

Endoglin (CD105) is an auxiliary membrane receptor of transforming growth factor

beta (TGF-beta) that interacts with type I and type II TGF-beta receptors and
modulates TGF-beta signaling. Endoglin is overexpressed in the tumor-associated
Endometriosis dan endoglin 2011.enl Page 29

vascular endothelium, where it modulates angiogenesis. This feature makes

endoglin a promising target for antiangiogenic cancer therapy. In addition, recent
studies on human and experimental models of carcinogenesis point to an important
tumor cell-autonomous role of endoglin by regulating proliferation, migration,
invasion, and metastasis. These studies suggest that endoglin behaves as a
suppressor of malignancy in experimental and human epithelial carcinogenesis,
although it can also promote metastasis in other types of cancer. In this review, we
evaluate the implication of endoglin in tumor development underlying studies
developed in our laboratories in recent years.

Reference Type: Journal Article

Record Number: 1

The role of the TGF-beta coreceptor endoglin in

Year: 2010

Author: E. Perez-Gomez, G. del Castillo, J. F. Santibanez, J. M. Lopez-Novoa, C.

Bernabeu and M. Quintanilla

Journal: ScientificWorldJournal
Volume: 10
Pages: 2367-84

Endoglin (CD105) is an auxiliary membrane receptor of transforming growth factor

beta (TGF-beta) that interacts with type I and type II TGF-beta receptors and
modulates TGF-beta signaling. Endoglin is overexpressed in the tumor-associated
vascular endothelium, where it modulates angiogenesis. This feature makes
endoglin a promising target for antiangiogenic cancer therapy. In addition, recent
studies on human and experimental models of carcinogenesis point to an important
tumor cell-autonomous role of endoglin by regulating proliferation, migration,
invasion, and metastasis. These studies suggest that endoglin behaves as a
suppressor of malignancy in experimental and human epithelial carcinogenesis,
although it can also promote metastasis in other types of cancer. In this review, we
evaluate the implication of endoglin in tumor development underlying studies
developed in our laboratories in recent years.

Reference Type: Journal Article

Record Number: 12
Endometriosis dan endoglin 2011.enl Page 30

Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin

and placental growth factor (PlGF) in preeclampsia
among high risk pregnancies
Year: 2010

Author: R. W. Powers, A. Jeyabalan, R. G. Clifton, P. Van Dorsten, J. C. Hauth, M.

A. Klebanoff, M. D. Lindheimer, B. Sibai, M. Landon and M. Miodovnik

Journal: PLoS One

Volume: 5
Issue: 10
Pages: e13263

BACKGROUND: Differences in circulating concentrations of antiangiogenic factors

sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are
reported to precede the onset of preeclampsia weeks to months in low-risk pregnant
women. The objective of this study was to investigate whether similar changes can
be detected in pregnant women at high-risk to develop the syndrome. METHODS:
This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent
preeclampsia in high-risk pregnancies. Serum samples were available from 194
women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal
gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples
collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and
PlGF. RESULTS: The odds of developing preeclampsia were significantly increased
among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the
ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly
decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82)
between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic
factors across gestation showed significant differences during the third trimester in
women who develop preeclampsia compared with appropriate controls in all
high-risk groups. However, when data were examined in relation to the gestational
week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5
weeks before the clinical onset of preeclampsia and only in women with previous
preeclampsia. CONCLUSIONS: The pattern of elevated concentrations of sFlt1 and
sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is
similar to that reported in low-risk pregnant women. However, differences in these
factors among high-risk women who do and do not develop preeclampsia are
modest, and do not appear to be clinically useful predictors in these high-risk
pregnant women.

Reference Type: Journal Article

Record Number: 32
Endometriosis dan endoglin 2011.enl Page 31

Correlation of circulating endoglin with clinical

outcome in biliary atresia
Year: 2010

Author: K. Preativatanyou, S. Honsawek, V. Chongsrisawat, P. Vejchapipat, A.

Theamboonlers and Y. Poovorawan

Journal: Eur J Pediatr Surg

Volume: 20
Issue: 4
Pages: 237-41

BACKGROUND AND AIM: Biliary atresia (BA) is a chronic progressive inflammatory

disorder of the extrahepatic and intrahepatic biliary system in children. The aim of
the present study was to investigate circulating endoglin levels in BA patients
compared with healthy controls and to determine the relationship between plasma
endoglin levels and outcome parameters of BA patients after Kasai operation.
METHODS: Fifty-five postoperative BA patients and 14 healthy controls were
recruited. The patients were divided into two groups based on their serum total
bilirubin levels (TB<34.2, no jaundice vs. TB>or=34.2 micromol/L, persistent
jaundice) and serum alanine aminotransferase (ALT<45, normal ALT vs. ALT>or=45
IU/L, high ALT). Circulating endoglin levels were analyzed by enzyme-linked
immunosorbent assay. RESULTS: Average levels of plasma endoglin were
significantly higher in BA patients compared to healthy controls (7.8+/-0.4 vs. 6.5+
-0.4 ng/mL; P=0.02). BA patients with persistent jaundice had higher plasma
endoglin levels than those without jaundice (9.2+/-0.8 vs. 6.9+/-0.3 ng/mL;
P=0.006). Furthermore, the concentrations of plasma endoglin in BA patients with
high ALT were significantly higher compared to those with normal ALT (8.5+/-0.5 vs.
6.3+/-0.5 ng/mL, P=0.003). In addition, BA patients with portal hypertension had
more elevated plasma endoglin levels than those without portal hypertension (8.8+
-0.6 vs. 6.1+/-0.3 ng/mL, P=0.001). Plasma endoglin was positively correlated with
serum ALT (r=0.36, P=0.007) and serum GGT (r=0.44, P=0.001). CONCLUSION:
High circulating endoglin correlated with a poor outcome for BA. Plasma endoglin
can be utilized as a potential biomarker reflecting the severity of ongoing liver injury
and biliary obstruction in BA patients after Kasai procedure.

Reference Type: Journal Article

Record Number: 2

Expression of midkine and endoglin in breast

carcinomas with different immunohistochemical
Year: 2011
Endometriosis dan endoglin 2011.enl Page 32

Author: L. Qin Li, H. L. Huang, J. L. Ping, W. Xu, J. Li and L. C. Dai

Journal: APMIS
Volume: 119
Issue: 2
Pages: 103-10

The aim of this study was to investigate the midkine and endoglin expression in
breast carcinomas with five different immunohistochemical profiles and their
relevance to histopathologic and clinicopathologic features. We analyzed 161
archival tissues immunohistologically. The level of midkine expression in breast
cancer significantly correlated with lymph node metastasis (p = 0.001) and TNM
staging (p = 0.003). High microvessel density (MVD) was associated with higher
midkine reactivity group (p = 0.036). Although the basal-like subtype had higher
midkine expression level and MVD, no significant difference with the other breast
cancer subtypes was found. In conclusion, midkine was a promising target for tumor
prognosis in clinical diagnosis and treatment. This study found no significant
differences in tumor angiogenesis in different molecular subtypes of breast cancer.

Reference Type: Journal Article

Record Number: 44

ALK5 phosphorylation of the endoglin cytoplasmic

domain regulates Smad1/5/8 signaling and
endothelial cell migration
Year: 2010

Author: B. N. Ray, N. Y. Lee, T. How and G. C. Blobe

Journal: Carcinogenesis
Volume: 31
Issue: 3
Pages: 435-41

Endoglin, an endothelial cell-specific transforming growth factor-beta (TGF-beta)

superfamily coreceptor, has an essential role in angiogenesis. Endoglin-null mice
have an embryonic lethal phenotype due to defects in angiogenesis and mutations
in endoglin result in the vascular disease hereditary hemorrhagic telangiectasia type
I. Increased endoglin expression in the proliferating endothelium of tumors has been
correlated with metastasis, tumor grade and decreased survival. Although endoglin
is thought to regulate TGF-beta superfamily signaling in endothelial cells through
regulating the balance between two TGF-beta-responsive pathways, the activin
receptor-like kinase 5 (ALK5)/Smad2/3 pathway and the activin receptor-like kinase
1 (ALK1)/Smad1/5/8 pathway, the mechanism by which endoglin regulates
Endometriosis dan endoglin 2011.enl Page 33

angiogenesis has not been defined. Here, we investigate the role of the cytoplasmic
domain of endoglin and its phosphorylation by ALK5 in regulating endoglin function
in endothelial cells. We demonstrate that the cytoplasmic domain of endoglin is
basally phosphorylated by ALK5, primarily on serines 646 and 649, in endothelial
cells. Functionally, the loss of phosphorylation at serine 646 resulted in a loss of
endoglin-mediated inhibition of Smad1/5/8 signaling in response to TGF-beta and
endothelial cell migration, whereas loss of phosphorylation at both serines 646 and
649 resulted in a loss of endoglin-mediated inhibition of Smad1/5/8 signaling in
response to bone morphogenetic protein-9. Taken together, these results support
endoglin phosphorylation by ALK5 as an important mechanism for regulating
TGF-beta superfamily signaling and migration in endothelial cells.

Reference Type: Journal Article

Record Number: 51

Endoglin phosphorylation by ALK2 contributes to

the regulation of prostate cancer cell migration
Year: 2010

Author: D. Romero, A. Terzic, B. A. Conley, C. S. Craft, B. Jovanovic, R. C. Bergan

and C. P. Vary

Journal: Carcinogenesis
Volume: 31
Issue: 3
Pages: 359-66

Endoglin, a transmembrane glycoprotein that acts as a transforming growth

factor-beta (TGF-beta) coreceptor, is downregulated in PC3-M metastatic prostate
cancer cells. When restored, endoglin expression in PC3-M cells inhibits cell
migration in vitro and attenuates the tumorigenicity of PC3-M cells in SCID mice,
though the mechanism of endoglin regulation of migration in prostate cancer cells is
not known. The current study indicates that endoglin is phosphorylated on cytosolic
domain threonine residues by the TGF-beta type I receptors ALK2 and ALK5 in
prostate cancer cells. Importantly, in the presence of constitutively active ALK2,
endoglin did not inhibit cell migration, suggesting that endoglin phosphorylation
regulated PC3-M cell migration. Therefore, our results suggest that endoglin
phosphorylation is a mechanism with relevant functional consequences in prostate
cancer cells. These data demonstrate for the first time that TGF-beta
receptor-mediated phosphorylation of endoglin is a Smad-independent mechanism
involved in the regulation of prostate cancer cell migration.

Reference Type: Journal Article

Record Number: 18
Endometriosis dan endoglin 2011.enl Page 34

Endoglin and CD-34 immunoreactivity in the

assessment of microvessel density in normal
pituitary and adenoma subtypes
Year: 2010

Author: F. Rotondo, S. Sharma, B. W. Scheithauer, E. Horvath, L. V. Syro, M.

Cusimano, F. Nassiri, G. M. Yousef and K. Kovacs

Journal: Neoplasma
Volume: 57
Issue: 6
Pages: 590-3

Vascularization is a prerequisite of tumor growth, invasion and metastasis. In the

present work, microvessel density was assessed by quantitating using two different
endothelial cell biomarkers, endoglin (CD-105) and CD-34. Fifty endocrinologically
active and 36 clinically nonfunctioning pituitary adenomas, all surgically resected, as
well as 10 autopsy-derived normal adenohypophyses were investigated by
immunohistochemistry. The results showed that in every pituitary adenoma type
endoglin, an assumed biomarker of proliferating endothelial cells, immunostained
fewer vessels than CD-34 which revealed immunopositivity in all capillaries.
Differences in endoglin versus CD-34 immunoexpression indicate varying degrees
of vascularity in pituitary adenoma subtypes. The low levels of endoglin
immunoexpression in pituitary tumors exposed to long-acting somatostatin analogs
and dopamine agonists are consistent with the view that these agents inhibit
angiogenesis. Keywords: immunohistochemistry, endoglin, CD34, microvascular
density, angiogenesis, pituitary.

Reference Type: Journal Article

Record Number: 13

The TGF-beta co-receptor endoglin modulates the

expression and transforming potential of H-Ras
Year: 2010

Author: J. F. Santibanez, E. Perez-Gomez, L. A. Fernandez, E. M. Garrido-Martin,

A. Carnero, M. Malumbres, C. P. Vary, M. Quintanilla and C. Bernabeu

Journal: Carcinogenesis
Volume: 31
Issue: 12
Pages: 2145-54
Endometriosis dan endoglin 2011.enl Page 35

Endoglin is a coreceptor for transforming growth factor-beta (TGF-beta) that acts as

a suppressor of malignancy during mouse skin carcinogenesis. Because in this
model system H-Ras activation drives tumor initiation and progression, we have
assessed the effects of endoglin on the expression of H-Ras in transformed
keratinocytes. We found that TGF-beta1 increases the expression of H-Ras at both
messenger RNA and protein levels. The TGF-beta1-induced H-Ras promoter
transactivation was Smad4 independent but mediated by the activation of the
TGF-beta type I receptor ALK5 and the Ras-mitogen-activated protein kinase
(MAPK) pathway. Endoglin attenuated stimulation by TGF-beta1 of both MAPK
signaling activity and H-Ras gene expression. Moreover, endoglin inhibited the Ras
MAPK pathway in transformed epidermal cells containing an H-Ras oncogene, as
evidenced by the levels of Ras-guanosine triphosphate, phospho-MAPK kinase
(MEK) and phospho-extracellular signal-regulated kinase (ERK) as well as the
expression of c-fos, a MAPK downstream target gene. Interestingly, in spindle
carcinoma cells, that have a hyperactivated Ras/MAPK pathway, endoglin inhibited
ERK phosphorylation without affecting MEK or Ras activity. The mechanism for this
effect is unknown but strongly depends on the endoglin extracellular domain.
Because the MAPK pathway is a downstream mediator of the transforming potential
of Ras, the effect of endoglin on the oncogenic function of H-Ras was assessed.
Endoglin inhibited the transforming capacity of H-Ras(Q61K) and H-Ras(G12V)
oncogenes in a NIH3T3 focus formation assay. The ability to interfere with the
expression and oncogenic potential of H-Ras provides a new face of the suppressor
role exhibited by endoglin in H-Ras-driven carcinogenesis.

Reference Type: Journal Article

Record Number: 38

Mechanism of the inhibitory effect of atorvastatin

on endoglin expression induced by transforming
growth factor-beta1 in cultured cardiac fibroblasts
Year: 2010

Author: K. G. Shyu, B. W. Wang, W. J. Chen, P. Kuan and C. R. Hung

Journal: Eur J Heart Fail

Volume: 12
Issue: 3
Pages: 219-26

AIMS: Transforming growth factor-beta1 (TGF-beta1) and endoglin play a causal

role in promoting cardiac fibrosis. Atorvastatin has been shown to have an inhibitory
effect on cardiac fibroblasts in vitro. However, the effects of statins on TGF-beta1
and endoglin are poorly understood. We therefore sought to investigate the
molecular mechanisms of atorvastatin on endoglin expression after TGF-beta1
Endometriosis dan endoglin 2011.enl Page 36

stimulation in cardiac fibroblasts. METHODS AND RESULTS: Cultured cardiac

fibroblasts were obtained from adult male Sprague-Dawley rat hearts. TGF-beta1
stimulation increased endoglin and collagen I expression and atorvastatin inhibited
the induction of endoglin and collagen I by TGF-beta1. Phosphatidylinositol-3 kinase
(PI-3) and Akt inhibitors (wortmannin and Akt inhibitor X) completely attenuated the
endoglin protein expression induced by TGF-beta1. TGF-beta1 induced
phosphorylation of PI-3 kinase and Akt, while atorvastatin and wortmannin and Akt
inhibitor X inhibited the phosphorylation of PI-3 kinase and Akt induced by
TGF-beta1. The gel shift and promoter activity assay showed that TGF-beta1
increased Smad3/4-binding activity and endoglin promoter activity, while
wortmannin and atorvastatin inhibited the Smad3/4-binding activity and endoglin
promoter activity induced by TGF-beta1. TGF-beta1 increased collagen I protein
expression, while endoglin siRNA attenuated collagen I protein expression induced
by TGF-beta1. Atorvastatin decreased left ventricular TGF-beta1, endoglin, and
collagen I protein expression and fibrotic area in a rat model of volume overload
heart failure. CONCLUSION: Atorvastatin inhibits endoglin expression through the
inhibition of PI-3 kinase, Akt, and Smad3 phosphorylation, and reduced Smad3/4
binding activity and endoglin promoter activity in cardiac fibroblasts.

Reference Type: Journal Article

Record Number: 20

Angiogenesis index CD105 (endoglin)/CD31

(PECAM-1) as a predictive factor for invasion and
proliferation in intraductal papillary mucinous
neoplasm (IPMN) of the pancreas
Year: 2010

Author: M. Tachezy, U. Reichelt, T. Melenberg, F. Gebauer, J. R. Izbicki and J. T.


Journal: Histol Histopathol

Volume: 25
Issue: 10
Pages: 1239-46

BACKGROUND: Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is

an increasingly diagnosed entity since its definition by the World Health
Organization in 1996. It has a broad clinical spectrum ranging from benign to
malignant tumors. Optimum treatment is controversial and a better understanding of
the development of IPMN of the pancreas and identification of potential prognostic
factors will help to address this. Angiogenesis plays an elementary role in the
development of malignant tumors and may well also be important in the
development of IPMN of the pancreas. Therefore we investigated endothelial cell
marker CD31 (PECAM-1) and angiogenesis associated marker CD105 (endoglin)
Endometriosis dan endoglin 2011.enl Page 37

by immunohistochemistry. METHODS: Thirty-two cases of surgically resected IPMN

were chosen retrospectively and clinical data were obtained. Specimens were
stained for proliferation marker (Ki-67), CD31 and CD105 by immunohistochemistry.
A CD105/CD31 Angiogenesis ratio (AR) was established to determine the
proliferating fraction of endothelial cells. RESULTS: The AR is significantly elevated
in invasive IPMN of the pancreas (Mann-Whitney-U Test, p<0.05) and is associated
with the Ki-67-labelling-index, demonstrating synergy between tumor-growth and
neovascularisation. Invasive IPMN of the pancreas is associated with significantly
lower recurrence-free and overall survival. CONCLUSIONS: Neovascularisation
plays an important role in the tumorigenesis of invasive IPMN of the pancreas, and
therefore angiogenesis-associated molecules like CD105 and CD31 might be useful
tools as prognostic markers. Furthermore, the results indicate a potential role for
adjuvant anti-angiogenic therapies in selected patients with recurring and/or
invasive IPMN of the pancreas.

Reference Type: Journal Article

Record Number: 24

Endoglin (CD105) expression and angiogenesis

status in small cell lung cancer
Year: 2010

Author: Y. Takase, K. Kai, M. Masuda, M. Akashi and O. Tokunaga

Journal: Pathol Res Pract

Volume: 206
Issue: 11
Pages: 725-30

It is well established that angiogenesis is crucial for tumor development and

progression. Among the angiogenesis immunomarkers defined to date, endoglin
(CD105) has been shown to be a useful marker of angiogenesis. To investigate the
degree of angiogenesis status in small cell lung cancer (SCLC) tissue, we assessed
35 cases of SCLC at autopsy using immunohistochemical staining of CD31 and
CD105. The intratumoral area, peritumoral area, and background pulmonary alveoli
were then observed under low magnification, and the microvessel density (MVD) for
each area was determined. The MVD-CD31 was the highest in the background
alveoli, followed by the intratumoral and peritumoral areas. The MVD-CD105 was
highest in the intratumoral area, followed by the peritumoral area and the
background lung. The ratio of CD105/CD31 revealed that almost 78% of the
intratumoral area, 63% of the peritumoral area, and 4.6% of the background lung
alveoli were newly formed and expressed CD105. This result indicated that SCLC is
predominantly supported by newly formed vessels that are generated by
CD105-mediated angiogenesis. These findings suggest that anti-angiogenic
therapy, especially CD105-targeting, may prove an effective form of SCLC
Endometriosis dan endoglin 2011.enl Page 38

Reference Type: Journal Article

Record Number: 43

Endothelial cells are activated during hypoxia via

endoglin/ALK-1/SMAD1/5 signaling in vivo and in
Year: 2010

Author: F. Tian, A. X. Zhou, A. M. Smits, E. Larsson, M. J. Goumans, C. H. Heldin,

J. Boren and L. M. Akyurek

Journal: Biochem Biophys Res Commun

Volume: 392
Issue: 3
Pages: 283-8

Endoglin (ENG) promotes angiogenesis by enhancing activation of TGF-beta type I

receptors ALK-1 and ALK-5. ALK-1 phosphorylates transcription factors SMAD1/5,
which bind to BMP-responsive elements (BRE), whereas ALK-5 phosphorylates
SMAD3, which binds to CAGA elements. Expression of ENG is increased during
myocardial infarction (MI). We investigated which ENG signaling pathway is
activated in endothelial cells during hypoxia. Expression of ENG, ALK-1, ALK-5, and
phosphorylated SMAD1/3/5 by immunostaining and immunoblotting in a mouse
model of myocardial infarction (MI) and in hypoxic human aortic endothelial cells
(HAECs) was evaluated. Activation of BRE and CAGA was measured by luciferase
assays in cells transfected with plasmids expressing ENG or ALK-1 and the number
of cells was quantified. mRNA expression of the target genes of TGF-beta signaling,
ID1 and BCL-X, was quantified by real-time RT-PCR. Expression of ENG, ALK-1
and phosphorylated SMAD1/5, but not ALK-5 or phosphorylated SMAD3, was
significantly increased in hypoxic endothelial cells in vivo and in vitro.
Overexpression of both ENG and ALK-1 significantly increased BRE but not CAGA
activity, expression of ID1 and BCL-X and the number of HAECs at hypoxia. ENG
ALK-1 signaling is one of the factors that regulate endothelial cell activity during
adaptive cardiac angiogenesis.

Reference Type: Journal Article

Record Number: 46
Endometriosis dan endoglin 2011.enl Page 39

Oxidative stress-induced S100B protein from

placenta and amnion affects soluble Endoglin
release from endothelial cells
Year: 2010

Author: E. Tskitishvili, N. Sharentuya, K. Temma-Asano, K. Mimura, Y.

Kinugasa-Taniguchi, T. Kanagawa, H. Fukuda, T. Kimura, T. Tomimatsu and K.

Journal: Mol Hum Reprod

Volume: 16
Issue: 3
Pages: 188-99

Oxidative stress with elevated intracellular Ca(2+) concentration as well as

endothelial dysfunction is a component of pre-eclampsia. Our aim was to investigate
the oxidative stress-dependent expression of Endoglin and Ca(2+)-binding S100B
protein from villous and amniotic tissue cultures, and to assess sEng expression
from S100B protein-stimulated endothelial cells. We initially examined Endoglin and
Hydroxy-nonenal-(HNE)-modified proteins in the placentas and amnion obtained
from women with pre-eclampsia (n = 8), and healthy controls (n = 8) by
immunohistochemistry. To examine oxidative stress and the S100B protein effect on
sEng expression from endothelial cells, normal villous and amniotic tissue cultures
were stimulated by 4-HNE, sodium fluoride and xanthine/xanthine oxidase, whereas
human umbilical vein endothelial cell cultures were treated with S100B protein in a
dose- and time-dependent manner at 37 degrees C in an environment of 95% air
and 5% of CO(2). Culture supernatants were assessed using ELISA. Cell viability
was determined using MTS assay. The concentrations of sEng and S100B protein
were significantly increased in the villous and amniotic tissue culture supernatants
under oxidative stress. S100B protein-stimulated endothelial cells released sEng
into conditioned media with a significantly higher expression levels at a
concentration of 200 pM-20 nM S100B by 2 h, whereas treated with 200 nM of
S100B endothelial cells significantly expressed sEng by 12 h and stimulated the cell
proliferation by the same period of time. Our findings show that oxidative stress
affects sEng and S100B protein expression from villous and amniotic tissues, and
picomolar and low nanomolar concentrations of S100B protein significantly
up-regulate sEng release from endothelial cells leading to endothelial dysfunction.

Reference Type: Journal Article

Record Number: 9

Endothelial cells of oral pyogenic granulomas

express eNOS and CD105/endoglin: an
immunohistochemical study
Endometriosis dan endoglin 2011.enl Page 40

Year: 2010

Author: S. I. Vassilopoulos, K. I. Tosios, V. G. Panis and J. A. Vrotsos

Journal: J Oral Pathol Med

J Oral Pathol Med (2010) Background: The pyogenic granuloma (PG) is a common
localized hyperplastic lesion of the oral cavity. The purpose of the present study was
to investigate the immunohistochemical expression of endothelial nitric oxide
synthases (eNOS) and CD105/endoglin in oral PGs, to evaluate their involvement in
the angiogenetic pathways of the lesion. Materials and Methods: Ninety-three PGs
were included in the study. Sixteen tumors were further sub-classified as pregnancy
tumors (PT) and seventeen as pyogenic granulomas with fibrosis (PGFM).
Immunohistochemical expression of eNOS and CD105/endoglin was quantified by
computerized image analysis with a semi-automated system. Percentage of staining
and number of objects (positive vessels) were recorded for each case. Results:
Intense eNOS expression was seen in 92 of 93 lesions. A statistically significant
association was found between eNOS percentage of staining/eNOS positive
vascular spaces (objects) and age of the patients (9% increase per decade of life).
Approximately 40% less eNOS positive objects were recorded in PGFM compared
with PGs. Intense membranous CD105/endoglin expression was seen in all cases.
The percentage of CD105/endoglin staining was statistically increased in PGs
compared with PT. Approximately 40% less CD105/endoglin objects were found in
PGFM compared with PGs; 56% more CD105/endoglin objects were found in
tongue lesions, compared with gingival lesions. There was no statistically significant
correlation considering percentage of staining and number of objects between
CD105/endoglin and eNOS. Conclusions: It is suggested that eNOS and CD105
endoglin are involved in the angiogenetic pathways of PG.

Reference Type: Journal Article

Record Number: 53

Elevated plasma endoglin (CD105) predicts

decreased response and survival in a metastatic
breast cancer trial of hormone therapy
Year: 2010

Author: M. N. Vo, M. Evans, K. Leitzel, S. M. Ali, M. Wilson, L. Demers, D. B.

Evans and A. Lipton

Journal: Breast Cancer Res Treat

Volume: 119
Issue: 3
Pages: 767-71
Endometriosis dan endoglin 2011.enl Page 41

Background Endoglin (CD105) is a co-receptor for TGF-beta, is expressed by

human vascular endothelial cells, and plays a major role in angiogenesis. Materials
and methods Pretreatment EDTA plasma from 224 metastatic breast cancer
patients enrolled in a phase III 2nd-line hormone therapy trial and 50 control
subjects were assayed for endoglin using an ELISA. Results The female control
group (n = 50) plasma endoglin upper limit of normal was defined as the mean + 2
SD (8.7 ng/ml). The breast cancer patient plasma endoglin was 6.40 +/- 2.23 ng/ml
(range 3.00-19.79 ng/ml). Elevated plasma endoglin levels were detected in 26 of
224 patients (11.6%). Patients with elevated plasma endoglin had a reduced clinical
benefit rate (CR + PR + Stable) (15 vs. 42%) (P = 0.01) to hormone therapy. TTP
was shorter for patients with elevated plasma endoglin, but did not reach statistical
significance (P = 0.2). Patients with elevated plasma endoglin had decreased overall
survival (median 645 vs. 947 days) (P = 0.005). Conclusion Elevated pretreatment
plasma endoglin levels predicted for decreased clinical benefit and a shorter overall
survival in metastatic breast cancer patients treated with 2nd-line hormone therapy.

Reference Type: Journal Article

Record Number: 41

Application of gene network analysis techniques

identifies AXIN1/PDIA2 and endoglin haplotypes
associated with bicuspid aortic valve
Year: 2010

Author: E. C. Wooten, L. K. Iyer, M. C. Montefusco, A. K. Hedgepeth, D. D. Payne,

N. K. Kapur, D. E. Housman, M. E. Mendelsohn and G. S. Huggins

Journal: PLoS One

Volume: 5
Issue: 1
Pages: e8830

Bicuspid Aortic Valve (BAV) is a highly heritable congenital heart defect. The low
frequency of BAV (1% of general population) limits our ability to perform
genome-wide association studies. We present the application of four a priori SNP
selection techniques, reducing the multiple-testing penalty by restricting analysis to
SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV
probands and 830 control subjects. Two knowledge-based approaches, CANDID
and STRING, were used to systematically identify BAV genes, and their SNPs, from
the published literature, microarray expression studies and a genome scan. We
additionally tested Functionally Interpolating SNPs (fitSNPs) present on the array;
the fourth consisted of SNPs selected by Random Forests, a machine learning
approach. These approaches reduced the multiple testing penalty by lowering the
fraction of the genome probed to 0.19% of the total, while increasing the likelihood
Endometriosis dan endoglin 2011.enl Page 42

of studying SNPs within relevant BAV genes and pathways. Three loci were
identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2
locus (p-value of 2.926x10(-06)) and a haplotype within the Endoglin gene (p-value
of 5.881x10(-04)) were found to be strongly associated with BAV. The Random
Forests approach identified a SNP on chromosome 3 in association with BAV
(p-value 5.061x10(-06)). The results presented here support an important role for
genetic variants in BAV and provide support for additional studies in well-powered
cohorts. Further, these studies demonstrate that leveraging existing expression and
genomic data in the context of GWAS studies can identify biologically relevant
genes and pathways associated with a congenital heart defect.

Reference Type: Journal Article

Record Number: 25

[Serum soluble Endoglin, plasma endothelin-1 and

coagulation function in early onset severe
preeclampsia with organ dysfunction]
Year: 2010

Author: L. J. Zhang, Y. H. Han and Y. Z. Han

Journal: Zhongguo Wei Zhong Bing Ji Jiu Yi Xue

Volume: 22
Issue: 6
Pages: 371-4

OBJECTIVE: To investigate the expression levels of serum soluble Endoglin (sEng),

plasma endothelin-1 (ET-1) and coagulation function in patients suffering from early
onset severe preeclampsia with organ dysfunction, and to analyze the clinical
significance. METHODS: Forty-nine early onset severe preeclampsia patients were
enrolled in the study group, including 26 cases without organ dysfunction (study
group I) and 23 cases with organ dysfunction (study group II). The control group
included 30 cases of health pregnant women during the same period of gestation.
The serum levels of sEng and plasma ET-1 were analyzed with enzyme-linked
immunosorbent assay (ELISA), coagulation function was determined at the same
time, and the relationship between the change in levels of sEng, ET-1, coagulation
function and organ function, and also outcome of perinatal infants. RESULTS: (1)
The levels of sEng, ET-1, fibrinogen (Fib) and mean platelet volume (MPV) of the
study group I and II were significantly higher compared with control group (sEng,
microg/L: 10.96+/-3.21, 14.17+/-4.02 vs. 7.49+/-2.73; ET-1, microg/L: 41.54+
-10.37, 65.91+/-12.46 vs. 24.56+/-6.26; Fib, g/L: 4.41+/-1.02, 5.35+/-1.17 vs. 3.69+
-0.82; MPV, fl: 11.71+/-1.21, 13.89+/-1.76 vs. 11.03+/-0.82, all P<0.05), and
prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet
(PLT) were significantly lower compared with control group (PT, s: 10.73+/-1.82,
8.37+/-1.51 vs. 12.95+/-1.91; APTT, s: 26.14+/-4.32, 22.69+/-3.77 vs. 30.25+/-4.71;
Endometriosis dan endoglin 2011.enl Page 43

PLT, x10(9)/L: 164.17+/-50.67, 136.43+/-51.21 vs. 201.63+/-59.83, all P<0.05).

There were also statistical significances in all the values between study group I and
II (all P<0.05). (2) There was positive correlation between the sEng level and
systolic pressure, diastolic pressure, Fib, urine protein of 24 hours, serum creatinine
(SCr); there was negative correlation between the sEng level and albumin (Alb)
content, PT, estriol/creatinine (E/C) of 12-hour urine, fetal birth weight (all P<0.01).
There was positive correlation between the level of ET-1 and the systolic pressure,
diastolic pressure, Fib, urine protein of 24 hours, SCr, or alanine aminotransferase
(ALT); there was negative correlation between the level of ET-1 and Alb, PT, E/C of
12-hour urine, or fetal birth weight (P<0.05 or P<0.01). (3)In the study group, the
occurrence rate of the heart, kidney and lung dysfunction, placental abruption and
perinatal death of infants increased (69.23% vs. 11.11%, 38.46% vs. 2.78%,
38.46% vs. 2.78%, 46.15% vs. 2.78%, 53.85% vs. 2.78%, all P<0.01) when the
content of sEng>or=16 microg/L compared with sEng<16 microg/L; the occurrence
rate of heart, kidney, liver and lung dysfunction, placental abruption and perinatal
death of infants increased (64.28% vs. 11.43%, 35.71% vs. 2.86%, 28.57% vs.
5.71%, 28.57% vs. 5.71%, 35.71% vs. 5.71%, 42.86% vs. 5.71%, all P<0.01) when
the level of ET-1>or=70 microg/L compared with ET-1<70 microg/L; the occurrence
rate of multiple organ dysfunction syndrome was 90% (9/10) when PT<7 s,
APTT<20 s and PLT<100x10(9)/L. CONCLUSION: The elevation of levels of serum
sEng, plasma ET-1 and coagulation abnormality may contribute to the pathogenesis
of the organ dysfunction in early onset severe preeclampsia, and the detection of
the above-mentioned indexes has important clinical value.

Reference Type: Journal Article

Record Number: 42

Angiotensin receptor agonistic

autoantibody-mediated tumor necrosis factor-alpha
induction contributes to increased soluble endoglin
production in preeclampsia
Year: 2010

Author: C. C. Zhou, R. A. Irani, Y. Zhang, S. C. Blackwell, T. Mi, J. Wen, H. Shelat,

Y. J. Geng, S. M. Ramin, R. E. Kellems and Y. Xia

Journal: Circulation
Volume: 121
Issue: 3
Pages: 436-44

BACKGROUND: Preeclampsia is a prevalent life-threatening hypertensive disorder

of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is
elevated in the blood circulation of women with preeclampsia and contributes to
disease pathology; however, the underlying mechanisms responsible for its
Endometriosis dan endoglin 2011.enl Page 44

induction in preeclampsia are unknown. METHODS AND RESULTS: Here, we

discovered that a circulating autoantibody, the angiotensin receptor agonistic
autoantibody (AT(1)-AA), stimulates sEng production via AT(1) angiotensin receptor
activation in pregnant mice but not in nonpregnant mice. We subsequently
demonstrated that the placenta is a major source contributing to sEng induction in
vivo and that AT(1)-AA-injected pregnant mice display impaired placental
angiogenesis. Using drug screening, we identified tumor necrosis factor-alpha as a
circulating factor increased in the serum of autoantibody-injected pregnant mice
contributing to AT(1)-AA-mediated sEng induction in human umbilical vascular
endothelial cells. Subsequently, among all the drugs screened, we found that hemin,
an inducer of heme oxygenase, functions as a break to control AT(1)-AA-mediated
sEng induction by suppressing tumor necrosis factor-alpha signaling in human
umbilical vascular endothelial cells. Finally, we demonstrated that the
AT(1)-AA-mediated decreased angiogenesis seen in human placenta villous
explants was attenuated by tumor necrosis factor-alpha-neutralizing antibodies,
soluble tumor necrosis factor-alpha receptors, and hemin by abolishing both sEng
and soluble fms-like tyrosine kinase-1 induction. CONCLUSIONS: Our findings
demonstrate that AT(1)-AA-mediated tumor necrosis factor-alpha induction, by
overcoming its negative regulator, heme oxygenase-1, is a key underlying
mechanism responsible for impaired placental angiogenesis by inducing both sEng
and soluble fms-like tyrosine kinase-1 secretion from human villous explants. Our
results provide important new targets for diagnosis and therapeutic intervention in
the management of preeclampsia.