Vascular Remodeling in Hypertension

Roles of Apoptosis, Inflammation, and Fibrosis

Hope D. Intengan, Ernesto L. Schiffrin

Abstract—Remodeling of large and small arteries contributes to the development and complications of hypertension. The
focus of this review is some of the mechanisms involved in the remodeling of small arteries in hypertension. In
hypertension, changes in small artery structure are basically of 2 kinds: (1) inward eutrophic remodeling, in which outer
and lumen diameters are decreased, media/lumen ratio is increased, and cross-sectional area of the media is unaltered;
and (2) hypertrophic remodeling, in which the media thickens to encroach on the lumen, resulting in increased media
cross-sectional area and media/lumen ratio. Growth, apoptosis, inflammation, and fibrosis contribute to vascular
remodeling in hypertension. Apoptosis is gene-regulated cell death, with minimal membrane disruption and
inflammation, that counters cell proliferation and fine-tunes developmental growth. Apoptosis has been reported in
hypertension to be both increased and decreased in different tissues, including blood vessels. Inflammation, which may
be low grade, probably plays an important role in triggering fibrosis in cardiovascular disease and hypertension.
Vascular fibrosis entails accumulation of collagen, fibronectin, and other extracellular matrix components in the vessel
wall and is an important aspect of extracellular matrix remodeling in hypertension. Associated with this, there may be
increases in cell-matrix attachment sites (integrins) and changes in their topographical localization that may modulate
arterial structure. Imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to
alteration in collagen turnover and extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of
the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood
vessel as smooth muscle cells are rearranged around a smaller lumen. The resulting remodeling of small arteries may
initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to
cardiovascular complications of hypertension. (Hypertension. 2001;38[part 2]:581-587.)
Key Words: arteries 䡲 apoptosis 䡲 inflammation 䡲 fibrosis 䡲 collagen 䡲 muscle, smooth
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I n hypertension, resistance arteries undergo eutrophic

and/or hypertrophic remodeling.1 In inward eutrophic re-
modeling, outer and lumen diameters are reduced, media
cross-sectional area is unaltered, and media/lumen ratio is
increased, without stiffening. Spontaneously hypertensive
(SHR)1,2 and 2-kidney, 1-clip Goldblatt3 rats, as well as mild
essential hypertensive patients,3,4 exhibit predominantly in-
ward eutrophic remodeling. When media growth encroaches
on the lumen to increase the media/lumen ratio, the change
has been called hypertrophic remodeling. It predominates in
severe hypertension, such as in deoxycorticosterone acetate
(DOCA)-salt rats,5 1-kidney, 1-clip (1K1C) Goldblatt rats,6 – 8
Dahl salt-sensitive rats,9 and humans with secondary hyper-
tension.10 Growth, apoptosis, inflammation, and fibrosis are
all mechanisms that have been invoked to contribute to
arterial remodeling in hypertension. Increased growth has
been classically implicated in arterial remodeling in hyper-
tension.11 Chronic vasoconstriction associated with mild in-
flammation and activation of deposition of collagen, fi-
bronectin, and other components of the extracellular matrix
may result in a remodeled arterial structure with a smaller
lumen and increased media/lumen ratio, ie, the inward eutro-
phic remodeled vessel. This review will center on events
taking place in the media of the vessel wall during vascular
remodeling. Although the endothelium may participate in
some of these effects to an important degree, its contribution
will only be addressed peripherally, and the reader is directed
to the many reviews on the subject.
Apoptosis
The finding that inward eutrophic remodeling may be pre-
dominant in some forms of hypertension has raised the
possibility that growth may be compensated or modified by
countervailing mechanisms in hypertension, particularly apo-
ptosis. Apoptosis is gene-regulated cell death, first recog-
nized in development as a mechanism involved in the
fine-tuning of growth.12 Apoptosis is also invoked in cancer,
immune diseases, Parkinson’s disease, and Alzheimer’s de-

Received March 27, 2001; first decision June 5, 2001; revision accepted July 18, 2001.
Metabolic Research Unit/Diabetes Center, University of California at San Francisco (H.D.I.); and Clinical Research Institute of Montreal (E.L.S.),
Montreal, Québec, Canada
Correspondence to Hope D. Intengan, PhD, Box 0540, Metabolic Research Unit/Diabetes Center, University of California at San Francisco, San
Francisco, CA 94143. E-mail intengh@itsa.ucsf.edu
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org

581
 582 Hypertension September 2001 Part II
mentia and has been reported to different degrees in athero-
sclerosis, restenosis, myocardial infarction, and heart failure.
Apoptosis is increased in hypertensive rat heart,13–16 brain,13
kidney,13,17 and arteries, where smooth muscle cell (SMC)
death modulates remodeling.18,19 Aortae of DOCA-salt rats,20
SHR,21 and angiotensin-infused rats22 exhibit apoptosis de-
tectable by DNA laddering, augmented in situ end-labeling of
fragmented DNA, and/or Bax/Bcl-2 ratio. Vascular SMC
cells in hypertensive rats are more prone to apoptosis, as
shown by serum deprivation of aortic SMC from stroke-prone
SHR (SHR-sp).23 In SHR, by 8 and 12 weeks but not 4 weeks
of age, blood pressure, small artery media/lumen ratio, and
apoptosis were increased.24 Enhanced apoptosis in resistance
arteries may be bed specific. In SHR small intramyocardial
arteries, the Bax/Bcl-2 ratio was reduced, suggesting de-
creased apoptosis,25 whereas arterioles and capillaries were
more prone to apoptosis, suggesting that in these beds,
apoptosis influences vascular resistance via rarefaction, as in
1K1C Goldblatt hypertensive rats.26
The role of apoptosis in vascular remodeling remains
unclear. In inward eutrophic remodeling, a combination of
growth and apoptosis, with apoptosis localized to the outer
periphery, reduces the outer diameter of the vessel, whereas
inward growth decreases lumen diameter, which may explain
the maintenance of media volume.27 Whether apoptosis is a
growth-related compensatory mechanism or a primary pro-
cess remains to be clarified. Interestingly, there are reports of
reduced SMC apoptosis in the small arteries of young SHR,
suggesting that a decrease in the apoptotic rate in resistance
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blood vessels contributes to their enhanced growth in this
model.28 Apoptosis modulators in the vasculature are numer-
ous and complex. Candidates may include reactive oxygen
species,29 NO,30 angiotensin type 2 (AT2) receptors,31 and the
endothelin system.32 Reactive oxygen species are involved in
the pathogenesis of hypertension and in apoptosis of vascular
cells, where, specifically, O2⫺ induces proliferation and H2O2
may induce apoptosis via a protein kinase C– dependent
mechanism.33 Angiotensin (Ang) II is also a potential trigger
of apoptosis.31,34 Ang II infusion in normotensive rats raised
blood pressure and increased apoptotic rate in thoracic aortae
by activation of angiotensin type 1 (AT1) and AT2 receptor
subtypes.22 Indeed, following AT1 receptor blockade in SHR,
vascular SMC apoptosis increased, an effect attenuated by
AT2 receptor antagonism.34 In rat aortic SMC, cyclic stretch
increased endothelin B (ETB) receptor mRNA and promoted
ligand occupancy of the resultant receptors by reducing
endothelin A (ETA) receptor mRNA. Exogenous endothelin
induced apoptosis via ETB receptors.32 On the other hand,
there is evidence for a survival and anti-apoptotic effect
mediated by endothelin A (ETA) receptors.19
Apoptosis, Vascular Remodeling, and Results
of Therapy
Vascular remodeling contributes to end-organ damage in
hypertension, providing a rationale for regression of remod-
eling of blood vessels as a therapeutic aim. Large conduc-
tance Ca2⫹ channel blockers stimulate SMC apoptosis, as
shown by studies with nifedipine35 and amlodipine21 on SHR
thoracic aorta SMCs and with verapamil on rat coronary
artery SMCs.36 During early treatment, ACE inhibition, AT1
receptor antagonism, and Ca2⫹ channel blockade stimulated
medial SMC apoptosis in thoracic aortae of SHR, although
mere blood pressure lowering by hydralazine had no effect.37
Some studies suggested that apoptosis occurs in waves for
limited periods.19,34,37 In other studies, increased apoptotic
rate persisted through 12 weeks of treatment with enalapril
and amlodopine21 and through 16 weeks with quinapril.38
Increased apoptosis also occurs in aortae of DOCA-salt rats,
and treatment with ETA-selective endothelin receptor antag-
onists enhances apoptosis in this model.19 Antihypertensive
therapy may therefore contribute to regression of vascular
wall growth via activation of pro-apoptotic mechanisms.
Inflammation
The actions of Ang II are mediated in large measure by
stimulation of production of superoxide anion and activation
of redox-sensitive genes.39 Some of these include genes
participating in inflammatory responses to angiotensin stim-
ulation.40 – 42 Among these are nuclear factor ␬B and AP-1,
associated with upregulation of adhesion molecules such as
intercellular adhesion molecule 1 and vascular cell adhesion
molecule 1, and stimulation of the production of chemokines
such as monocyte chemotactic protein 1 followed by recruit-
ment of monocytes/macrophages to the vascular wall. In rats
doubly transgenic for human renin and human angioten-
sinogen, which develop a malignant form of hypertension,
inflammatory mediators were shown to be activated, with
upregulation of adhesion molecules in the kidney and infil-
tration by monocyte-macrophages.43 Although the latter pro-
cesses and the role of Ang II in triggering them have been
clearly identified in the heart and kidney43 and play a role in
the progression of atherosclerosis in large conduit vessels,44
their participation in small artery remodeling is only now
starting to be investigated. However, we have often noted that
in small arteries, increased numbers of inflammatory cells
may be observed in hypertension in the adventitia, an often
neglected layer of the vascular wall. Indeed, the adventitia
has recently been identified as an important source of oxygen
free radicals potentially participating in vascular pathophys-
iology.45 It is likely that inflammation and the increased
oxidative stress, which probably act as an important trigger
and may to a large extent be Ang II– dependent, play a role in
the process leading to remodeling of small and large vessels
in hypertension.46 Nonetheless, this remains to be further
investigated. As well, the potential importance of inflamma-
tion in the vascular wall from a therapeutic viewpoint remains
an interesting but largely unexplored area of potential appli-
cation of the new knowledge of participation of inflammatory
mediators in remodeling of the vasculature.
Vascular Fibrosis
Fibrillar extracellular matrix in the vessel wall includes
structural proteins (collagen and elastin) and adhesive pro-
teins (eg, laminin and fibronectin). In hypertension, vascular
fibrosis entails in large part, the deposition of extracellular
matrix, particularly collagen, in the arterial wall. In normal
arteries, fibrillar collagens I and III are major constituents of
the intima, media, and adventitia, whereas types I, III, IV, and
 Intengan and Schiffrin
V are in endothelial and SMC basement membranes.58 There
are early reports47,48 of increased collagen synthesis in the
arterial wall in hypertension that occurred globally in SHR
and DOCA-salt rat aortae, mesenteric arteries, cerebral mi-
crovessels, pial arteries, and basilar arteries. Collagen accu-
mulation may not follow synthesis and may be bed specific,
as it occurs in coronary arteries49 but less consistently in
aortae of SHR50 or DOCA-salt rats,51 although recent studies
report increases in collagen III but not collagen I in Japanese
and Lyon SHR strains.52 In SHR-sp aortae, total collagen is
not augmented.53 Nonetheless, upregulated gene expression
of types I, III, and IV was detected in aortae and mesenteric
arteries.54 Collagen was reported increased in mesenteric
small arteries of SHR55,56 or subcutaneous resistance arteries
from essential hypertensive humans.57 Collagen is the extra-
cellular fibrillar component that may alter the passive pres-
sure/diameter relation of arteries at higher pressures and
induce a progressive stiffening of the vascular wall. However,
we showed in small arteries from these relatively young
humans with mild to moderate hypertension that increased
collagen deposition may be associated with reduced stiff-
ness.57 This indicates that it is not the amount of collagen in
the wall but rather the recruitment of collagen fibers at higher
pressures that results in increased stiffness of the vessel wall.
Early in hypertension, both in experimental animals and in
humans, the vessel wall components may be less stiff in spite
of increased collagen deposition, but as hypertension
progresses, other changes, particularly in extracellular ma-
trix–SMC anchoring, may result in normalization of wall
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stiffness.58 Later, the increased stiffness that occurs in ad-
vanced hypertension may develop.59 Fibronectin also accu-
mulated in DOCA-salt,60 SHR,61 Dahl salt-sensitive,62 SHR-
sp,63 and Ang II–infused rat aortae,64 probably independently
of blood pressure. In many of these models, stimulation of
AT1 receptors is the likely mechanism. However, the extent to
which fibronectin accumulates in resistance arteries in hyper-
tension is presently unclear, although we have preliminary
evidence (Q. Pu and E.L. Schiffrin, unpublished, 2001) using
confocal microscopy that demonstrated increased fibronectin
in the media of resistance arteries of SHR-sp.
Ang II stimulates human vascular SMC production of
collagen I,65 activating the procollagen type I gene via the
mitogen-activated protein kinase/ERK pathway.66 These ef-
fects are mediated, at least in part, by AT1 receptors.62,64,65
AT2 receptors may also play a role67,68 via G␣I proteins.69
Involvement of angiotensin evokes the possible involvement
of multiple autocrine growth factors that modulate the re-
sponses to angiotensin, such as transforming growth factor–␤
(TGF-␤) and platelet-derived growth factor,70 as well as other
growth factors, including insulin-like growth factor and basic
fibroblast growth factor. Ang II increased TGF-␤ in a
losartan-sensitive manner, and in human arterial SMC,
angiotensin-stimulated collagen synthesis was inhibited by
blocking TGF-␤.71 A relationship between Ang II and TGF-␤
was suggested previously, in which stretch was the experi-
mental stimulus of collagen synthesis in rabbit aortic SMC.72
Stretch concomitantly increased immunoreactive Ang II and
TGF-␤ in the culture medium, and elicited collagen synthesis.
Angiotensin antagonism attenuated TGF-␤ secretion and
Vascular Remodeling in Hypertension 583
collagen synthesis. Collagen synthesis was inhibited by
TGF-␤ neutralizing antibody or truncated TGF-␤ type II
receptor, suggesting a linear pathway where Ang stimulates
TGF-␤ secretion, which in turn triggers collagen synthesis.
Indeed, exogenous TGF-␤ in aortic SMC results in collagen
synthesis,72 and in human cells, a role of TGF-␤ in stretch-
induced collagen synthesis was also detected.73 However, in
SHR SMC these effects of TGF-␤ were blunted versus
WKY.74
Other modulators of collagen synthesis include aldosterone
and endothelin. Aortic collagen accumulation was attenuated
by inhibiting ACE21 or by antagonizing aldosterone.75 Colla-
gen I synthesis is stimulated by endothelin-1 (ET-1) in
coronary artery SMC.76 Indeed, in the N␻-nitro-L-arginine
methyl ester (L-NAME) model of hypertension, ET-1 syn-
thesis is increased in renal microvessels and activates local
collagen formation.77 Losartan blocked L-NAME–induced
fibrosis, and stimulatory effects of angiotensin on collagen
I-␣2 chain promoter activity were attenuated by endothelin
receptor antagonism.78 In DOCA-salt hypertensive rats,
which have very significant cardiac fibrosis, administration of
an ETA receptor antagonist ameliorated interstitial and
perivascular fibrosis.79 In aldosterone-infused rats, vascular
changes were prevented by endothelin antagonism,80 and
collagen deposition in heart and arteries was also demon-
strated to be endothelin dependent.81 Cardiovascular fibrosis
is, in large part, a humoral-determined event, with central
roles of Ang II, ET-1, and mineralocorticoids.
Matrix metalloproteinase (MMP) activity may modulate
hypertension-related accumulation of extracellular matrix pro-
teins in resistance arteries. MMPs are Zn2⫹- and Ca2⫹-dependent
proteolytic enzymes that degrade extracellular matrix pro-
teins.82,83 Several different MMPs are present in the vasculature.
These include collagenases (eg, interstitial collagenase MMP-1
and MMP-13) that digest structural or fibrillar collagens (types
I to III). Gelatinases A (MMP-2) and B (MMP-9), which digest
denatured collagen (gelatin) and collagen types IV and V, are
found in the subendothelial basement membrane. Stromelysins
(eg, MMP-3) are also found. They digest adhesive molecules
such as laminin, fibronectin, nonfibrillar collagens, and proteo-
glycans. Finally, there are the membrane-type MMPs (MT1-
MMP or MMP-14). MT1-MMP activates other MMPs.84 MT1-
MMP and MMP-2 act as an integral part of multiprotein
enzymatic complex. MT1-MMP may activate latent MMP-13,
which in turn activates MMP-9. MT1-MMP may form a ternary
complex with tissue inhibitors of metalloproteinase (TIMP)-2
and pro-MMP-2 that depends on the tethering of pro-MMP-2 by
␣v␤3-integrin. Indeed, a number of integrins, including ␣5␤1, may
be involved in activation of MMPs. MMP-mediated modulation
of extracellular matrix could result via integrin-mediated signal-
ing in cytoskeletal reorganization. This could contribute to both
differential restructuring of extracellular matrix proteins and
reorganization of SMCs in the vascular wall in hypertension. In
serum from SHR with extensive myocardial fibrosis85,86 and in
humans with essential hypertension,87 markers of enhanced
synthesis of type I collagen are not balanced by markers of
increased type I collagen degradation. In hypertensive patients in
whom type I collagen precursors were augmented, serum con-
centrations of MMP-1 were in fact reduced.88 MMP-1 activity
 584 Hypertension September 2001 Part II
was decreased in the mesenteric arterial bed of young SHR
before hypertension was established.89 MMP-3 activity was also
decreased, which may promote accumulation of fibronectin and
proteoglycans in SHR.90,91 Pro-MMP2 and activated MMP-2
activities were diminished in mesenteric arteries from adult
SHR,89 which could facilitate accumulation of types IV and V
collagen and fibronectin.54 Changes in MMP activity may thus
contribute to resistance artery remodeling in hypertension by
modulating extracellular matrix profile and interacting with
adhesion receptors. Significant decreases in MMP activity in
young SHR-sp vessels could result in decreased collagen turn-
over and increased collagen accumulation, whereas in the older
hypertensive rats, vascular increased MMP activity suggests
countervailing activation of MMPs or inhibition of activity of
TIMPs to reduce collagen accumulation in the vascular wall.
We have proposed that remodeling of the small arteries
occurring in both humans and experimental models of hyper-
tension implies a remodeling of the extracellular matrix and
of extracellular–vascular SMC attachment sites and a restruc-
turing of vascular SMCs that may in part be triggered by the
adhesion molecules that mediate anchoring to ECM compo-
nents. These adhesion molecules (integrins) transduce signals
from the extracellular to the cytoskeletal fibrillar compo-
nents.27 Because of changes in extracellular matrix compo-
nents and corresponding adhesion receptors, interactions
between SMCs and matrix proteins shift, quantitatively
and/or topographically, resulting in a rearrangement of SMCs
and a restructured vascular wall. We hypothesized that
vascular remodeling may involve changes in these attachment
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sites. We have shown that expression of integrins is abnormal
in SHR blood vessels and is modulated by age.55 Mesenteric
arteries from SHR exhibited an increase in expression of
␣v␤3- and ␣5␤1-integrins from 6 to 20 weeks. In arteries from
adult SHR, the volume density of collagen was significantly
increased.55 Bézie et al50 have also reported increases in
␣5-integrins and fibronectin, their main ligand, in aorta from
SHR. Such changes may represent an increase in cell–
extracellular matrix attachment sites and perhaps also their
topographical localization that may modulate arterial struc-
ture. One may envision that in the hypertensive state, pro-
gressive deposition of extracellular matrix fibrillar compo-
nents anchored to SMCs of the chronically constricted vessel
may result in an artery with a persistently smaller lumen, as
found in the inward eutrophic remodeling characteristic of
small arteries of SHR and in essential hypertension. In
addition, changes in the attachment of the fibrillar elements of
the matrix may occur that contribute to arterial inward
remodeling by altering the anchoring of SMC to fibrillar
components of the extracellular matrix. This would also alter
signal transduction by integrins from outside the cell to the
SMC cytoskeleton, promoting restructuring of the SMC in the
vessel wall.
Growth of the smooth muscle in the media of blood vessels
may be facilitated by several extracellular matrix proteins.
Tenascin-C, an extracellular matrix glycoprotein and ligand
for ␣v␤3, is one such extracellular component that may be
important in vascular remodeling in hypertension. It co-
localizes with proliferating SMCs in SHR92 and may be a
survival factor that promotes proliferation and protects SMCs
from apoptosis. Fibronectin matrix assembly may likewise
facilitate vascular SMC growth. As mentioned previously,
total fibronectin50 and ␣5␤1-integrins50,55 are increased in
arteries of SHR. This suggests that fibronectin matrix assem-
bly, which requires the interaction between the arginine-
glycine-aspartate site of fibronectin and ␣5␤1-integrins,93 is
also elevated in SHR vessels. Another arginine-glycine-
aspartate– containing protein that may be associated with
proliferation is osteopontin, a secreted glycoprotein adhesive
for vascular SMCs via ␣v␤3-integrins.94 In vitro studies have
demonstrated that osteopontin overexpression is associated
with arterial SMC proliferation.95
Fibrosis, Vascular Remodeling, and Therapy
Arterial wall thickening may increase peripheral resistance
and blood pressure, in part by physically encroaching on the
lumen and, where collagen is invoked, by increasing wall
stiffness to reduce lumen diameter at a given pressure.27 In
SHR resistance arteries, collagen density or relative content
was normalized by ACE inhibition,55,56 AT1 receptor block-
ade,55 and the dihydropyridine Ca2⫹-channel blocker amlo-
dipine.56 Aldosterone antagonism also reduced collagen in
SHR aortae.96 Likewise, in vessels from SHR-sp and DOCA-
salt rats, AT1 receptor antagonism reduced collagen types I,
III, and IV mRNA.63,97 At least in SHR, amelioration of
collagen accumulation is not due to blood pressure lowering
per se, as minoxidil had no effect on collagen content in
aortae or in renal and superior mesenteric arteries.98 Thus,
regression of vascular fibrosis may occur independently of
blood pressure lowering.
Conclusion
In hypertension, vascular remodeling contributes to increased
peripheral resistance, impacting both development and com-
plications of hypertension. Although growth is the mecha-
nism that is more classically associated with vascular remod-
eling, it has increasingly been appreciated that apoptosis,
low-grade inflammation, and vascular fibrosis are dynamic
processes that also may influence the degree of remodeling
that occurs (summarized in the Figure). Inward growth may
be associated with peripheral apoptosis, contributing to eu-
trophic remodeling. Low-grade inflammation, perhaps angio-
tensin- or endothelin-dependent and triggered in part by
increased oxidative stress in the vascular wall stimulated by
these peptides or other agents, may elicit growth factor–
mediated extracellular matrix remodeling. Changes in the
anchoring of cells to extracellular fibrillar components may
alter cell attachment, changing the architecture of the vessel
wall, and may promote abnormal intracellular transduction of
extracellular input to the cytoskeleton of SMC, contributing
to SMC cell restructuring. Chronic vasoconstriction may
result in an inwardly remodeled blood vessel as the con-
tracted vessel structure becomes embedded in a remodeled
extracellular matrix, further promoting re-arrangement of
SMCs around a smaller lumen. Growth, apoptosis, inflamma-
tion, and fibrosis of blood vessels may thus all contribute to
vascular remodeling. The resulting arterial remodeling may
initially be adaptive but eventually becomes maladaptive and
compromises organ function, contributing to cardiovascular
 Intengan and Schiffrin
Proposed model of the pathophysiologic mechanisms leading to
small artery remodeling in hypertension. Blood pressure (BP)
may rise progressively as a result of genetically and/or environ-
mentally determined increased neurohumoral/hormonal (endo-
crine, paracrine, or autocrine) drive. Either directly or indirectly
via the action of vasoactive peptides such as Ang II and ET-1,
mediated in part by increased oxidative stress, vasoconstriction
is induced and SMC growth and apoptosis, low-grade inflam-
mation, and vascular fibrosis occur, leading to vascular remod-
eling. Vascular remodeling may feed back by amplifying BP ele-
vation. SMC growth and apoptosis, low-grade inflammation, and
vascular fibrosis are dynamic processes that influence vessel
remodeling. Inward growth associated with peripheral apoptosis
may lead to eutrophic remodeling. Low-grade inflammation, per-
haps triggered by Ang II or ET-1 stimulation of oxidative stress
in the vascular wall, may promote growth factor–mediated
extracellular matrix remodeling. Changes in the anchoring of
cells to extracellular fibrillar components may alter extracellular-
Downloaded from http://ahajournals.org by on October 6, 2023
SMC attachments (integrins), changing the architecture of the
vessel wall, and the intracellular transduction of extracellular sig-
nals to the SMC cytoskeleton, favoring restructuring of SMC
cells. Changes in MMP/TIMPs may contribute to alteration in
collagen turnover and promote extracellular matrix remodeling.
Chronic vasoconstriction may lead to embedding of the con-
tracted vessel structure in a remodeled extracellular matrix, con-
tributing to the inward remodeling of the blood vessel as SMCs
become rearranged around a smaller lumen. Growth, apoptosis,
inflammation, and fibrosis in the blood vessel wall may thus all
contribute to vascular remodeling. Although not developed in
the text, endothelial dysfunction, in part induced by BP eleva-
tion and mediated by reduced NO bioavailability as NO is scav-
enged by oxygen free radicals, also promotes remodeling. NO
would under normal conditions inhibit vasoconstriction, growth,
and collagen deposition and promote apoptosis. Remodeling
may initially be adaptive but eventually becomes maladaptive
and compromises organ function, contributing to cardiovascular
complications of hypertension.
complications of hypertension. Accordingly, growth, apopto-
sis, inflammation, and fibrosis all are important end points
and attractive therapeutic objectives in hypertensive vascular
disease.
Acknowledgments
The authors’ work was supported by grants 13570 and 37917 and a
group grant to the Multidisciplinary Research Group on Hyperten-
sion to E.L.S., all from the Canadian Institutes of Health Research
(CIHR, previously Medical Research Council of Canada). H.D.I.
was supported by a Centennial Fellowship (now entitled Senior
Research Fellowship) from CIHR.
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