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See the related articles beginning on pages 649 and 707. ease, reminiscent of preeclampsia in
humans. In another study in this
Soluble VEGF receptor Flt1: the elusive issue, V. Eremina et al. (5) provide
additional evidence for a critical role
preeclampsia factor discovered? of VEGF in renal disease during
preeclampsia. These authors demon-
strate that mice lacking one VEGF
Aernout Luttun and Peter Carmeliet allele in renal podocytes develop the
typical renal pathology found in preg-
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute
for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium
nant women with preeclampsia. These
studies therefore shed unprecedented
J. Clin. Invest. 111:600–602 (2003). doi:10.1172/JCI200318015. light on the pathogenesis of pre-
eclampsia and offer novel therapeutic
opportunities for this disease.
The occurrence of seizures (eclampsia, termed the “disease of theories,” as
from the Greek “eklampsis,” sudden several models for its pathogenesis sFlt1: a likely candidate
flashing) has been a long-known and have been proposed. But, as of today, preeclampsia factor
feared complication of pregnancy, no satisfactory unifying hypothesis For the fetus to develop normally, it
often killing both mother and child. has emerged (1). The restricted occur- must receive sufficient oxygen and
Preeclampsia, or the condition pre- rence of preeclampsia to humans and nutrients (6). These are supplied via the
ceding full-blown eclampsia, affects primates and the lack of a suitable maternal spiral arteries in the uterus.
up to 5% of pregnant women and is animal model have hampered the During normal pregnancy, cytotro-
diagnosed by the onset of hyperten- understanding of its pathogenesis (3). phoblasts convert from an epithelial to
sion and proteinuria in the second In this issue of the JCI, S.E. Maynard an endothelial phenotype (a process
trimester (1). Preeclampsia may even- et al. (4) report the novel insight that termed pseudo-vasculogenesis) and
tually progress to glomerular mal- circulating levels of two angiogenic invade maternal spiral arteries. This
function, thrombocytopenia, liver and growth factors, VEGF and placental vascular remodeling increases the bulk
brain edema, and associated life- growth factor (PlGF), may play a more flow and the supply of nutrients and
threatening seizures (2) (Figure 1). important role than previously oxygen to the fetus by the end of the
Preeclampsia has been sometimes believed. In particular, the authors first trimester (7, 8) (Figure 1). Vascular
propose that, in pregnant women factors such as VEGF, angiopoietins,
with preeclampsia, the placenta pro- and ephrins have been implicated in
Address correspondence to: Peter Carmeliet, duces elevated levels of the soluble this process (7). In preeclampsia, pseu-
Center for Transgene Technology and Gene fms-like tyrosine kinase 1 (sFlt1) do-vasculogenesis is defective, and the
Therapy, Flanders Interuniversitary Institute
receptor, which captures free VEGF resultant placental ischemia has been
for Biotechnology, Katholieke Universiteit
Leuven, Campus Gasthuisberg, Herestraat 49, and PlGF. As a result, the normal vas- proposed to trigger the release of
B-3000, Leuven, Belgium. culature in the kidney, brain, lungs, unknown placenta-derived factors. The
Phone: 32-16-34-57-72; Fax: 32-16-34-59-90; and other organs is deprived of essen- latter would induce systemic endothe-
E-mail: tial survival and maintenance signals lial dysfunction and thereby contribute
Conflict of interest: The authors have
declared that no conflict of interest exists.
and becomes dysfunctional (Figure 1). to the renal, cardiovascular, and neu-
Nonstandard abbreviations used: placental As the authors show in their rodent rological defects of preeclampsia (Fig-
growth factor (PlGF); fms-like tyrosine model, this may lead to the develop- ure 1). Despite intensive efforts, the
kinase 1 (Flt1); soluble Flt1 (sFlt1). ment of hypertension and renal dis- precise nature of the placenta-derived

600 The Journal of Clinical Investigation | March 2003 | Volume 111 | Number 5

when VEGF levels in the renal 2. these authors VEGF levels mediate angiogenesis in neovascularization. Thus. the uterine spiral arteries are infiltrated and remodeled by endovascular invasive trophoblasts. Results VEGF and its homologue PlGF. currently may have discovered a likely candi. perhaps not all. plasma levels rise. and a circulating VEGF and PlGF levels surrogate markers of the success of soluble secreted ectodomain which below a critical threshold required for anti-angiogenesis therapy — the only captures VEGF and PlGF (sFlt1). At the very least. elevated sFlt1 levels in the placenta resulting in placental hypoxia. (a) During normal pregnancy. increased amounts of soluble Flt1 (sFlt1) are produced would not further aggravate the dis- by the placenta and scavenge VEGF and PlGF. Flt1. It remains unknown whether hypoxia is the trigger for stimulating sFlt1 secretion in the spiral artery remodeling. chronic administra- In their study. glomerular endothelial cells swell. 2002. general endothelial dysfunction disease. since the placenta is hypoxic in preg- Figure 1 nant women with preeclampsia.W. may pose a risk of women with preeclampsia produced disease. sia? Whereas dynamic surges of high potential to inhibit cancer. hav. explaining. J. The Journal of Clinical Investigation | March 2003 | Volume 111 | Number 5 601 . This altered balance causes generalized endothelial dysfunction. J. but at least several. We previously demonstrated that absence of the VEGF164 and VEGF188 isoforms impairs glomerular filtration (9). and chronic report that the placenta of pregnant the embryo and in the adult during inflammation. It also blood flow significantly in order to meet the oxygen and nutrient demands of the fetus. of the hallmark symp- toms of preeclampsia. result in preeclampsia and thereby improve Flt1 and fetal liver kinase-1. Pathogen- esis and genetics of pre-eclampsia. studies suggest? First. they may reduce the and blood pressure might be used as mits angiogenic signals (Flt1). and hypertension. the chances of the mother and child though sFlt1 may be one of the few. renal insuf- increased levels of sFlt1. D.. By inducing vaso- dilation. maintenance of the established vascu. (b) In the remains to be determined whether the placenta of preeclamptic women. thereby lowering circulating levels of unbound VEGF ease by impairing VEGF-dependent and PlGF. and thus lower circulating VEGF levels will cause elevated blood pres- sure. resulting in multi-organ pseudo-vasculogenesis and maternal disease. whether it might contribute to any dosage–dependent control of VEGF. That is. prodocytes drop 50%. Maynard et al. Preeclampsia. Indeed. retinal ing used gene profiling. when sFlt1 this notion. In addition. inhibitor of VEGF demonstrate that glomerular capillary known today. the sFlt1 hypothesis allows the proposal of a unifying model. not the only. renal parameters receptor tyrosine kinase which trans. As insightful as these studies are. continuous low levels of endothelial dysfunction. placenta of preeclamptic mothers and whether the higher sFlt1 levels interfere with trophoblast What medical implications do these invasion and spiral artery remodeling. thereby increasing be responsible (Figure 1). VEGF also induces hypoten- sion. (5) for a healthy future. 357:53–56. Hypox- ia upregulates Flt1 expression and.. (4) How then can elevated circulating lev.B. 2001. sort of human disease. Pridjian. G. they do not address the question as to what upregulates sFlt1 expression in the placenta in preeclampsia. strategies designed to normalize circulating free VEGF and PlGF levels might be preeclampsia factors has remained Altered angiogenic balance causes expected to halt progression of the enigmatic for years. and Puschett. it remained unknown function is under the strict gene. Roberts. Thus. and proteinuria develops — as in preeclampsia. its lature in the adult. els of sFlt1 contribute to preeclamp. Indeed. Even edema in the liver. Lancet. The resultant such markers. Third. angiogenesis field desperately needs As sFlt1 lacks a cytosolic domain. exists cells to survive prolonged periods and from ongoing clinical trials support in two forms: a membrane-bound function properly. being evaluated for their therapeutic date preeclampsia factor. tion of VEGF inhibitors. these function is restricted to regulating endothelial dysfunction may disrupt studies raise new hopes that novel (reducing) the levels of free VEGF and the blood-brain barrier and cause strategies may be designed to combat PlGF available to signal via intact intracranial hypertension. trophoblast invasion does not occur and blood flow is reduced. 1. could Hypothesis on the role of sFlt1 in preeclampsia. if lar function. binding VEGF are required for endothelial ficiency. Endothelial dysfunction may also deregulate hemostasis and trigger thrombocytopenia. and affect glomeru.M. Eremina et al. and Cooper. another hallmark of preeclamp- sia. capillary loops collapse. Second.

J.F. Ultrastructural differentiation of enzymes. 13:1548–1560. were again a calcium phosphate com- icant. Excess placental soluble stromal and vascular components in early Pathol. 178:30–44. intestinal bypass procedure. promoted heterogeneous nucleation USA. Clin. E. due to sequent extension to the vasa recta. cytotrophoblast survival are dysregulated in mal models of preeclampsia. These investigators per- formed kidney biopsies on stone- forming patients to determine the Most cases of nephrolithiasis are asso. reported Strong Memorial Hospital. and Losonczy. which afflicts approximately 50% of stone formers within five years of David A. Contact of these crystals Medicine and Dentistry. Randall demon. et al. USA in this issue of the JCI (7). Ani. the initial crystals Randall’s plaques. Nephrology Unit. with urine. V. Evan et al.P. to the papillae. Loss of the VEGF(164) and endothelial dysfunction. Cell. these and other causes of nephrolithi. et al. Rochester. stone formers (2). Mol. the site of the initial solid phase er. 1987. In patients strated that interstitial crystals located could either be endocytosed or remain with hyperoxaluria resulting from at. we did not have an answer to this rather elemen- J. B. New York. Am. J. Eremina. genital and acquired renal diseases. fms-like tyrosine kinase 1 (sFlt1) may contribute to macaque placental villi. to calcium oxalate. the most common solid phase areas adjacent to Randall’s plaques in hypercalciuria (1). 2003. Thus there are different sites of initial 602 The Journal of Clinical Investigation | March 2003 | Volume 111 | Number 5 . to pre-eclampsia. He found that these anatomical site and composition of ciated with the relatively common crystals were composed not of calcium the initial solid phase. doi:10.. See the related article beginning on page 607. tary question. These patients gen. Y. V. found in patients with nephrolithiasis. they subse. Where is the site of initial crystalliza. lumen. 57:598–618. Clin. In hypercalciuric dietary calcium leading to increased believed that the calcium phosphate calcium oxalate stone formers. Bushinsky the initial stone (6).. 2002. Goldman-Wohl. which also cases. there was insuffi. (apatite) crystallization in the base- and calcium phosphate. or adjacent to. ations of VEGF-A expression lead to distinct con. tured tubular cells (5). ducts. Non- Fax: (585) 442-9201. New York 14642. may have promot- has long been the subject of debate. found initial calcium phosphate ration with respect to calcium oxalate stitium and then eroded into the uri. severe preeclampsia and hemolysis. rounding the terminal collecting urine oxalate excretion and supersatu. Mattot. stone formation was unlikely. 601 Elmwood tion — the interstitium. D. Regulation VEGF(188) isoforms impairs postnatal glomeru- teinuria in preeclampsia. or perhaps the renal calyx. Rochester. excretion into the ureter? Knowing the stone formers. patients undergoing percutaneous erally absorb an excess amount of but of calcium phosphate (3).. This would help them to devise effective therapy aimed solid phase at preventing recurrent nephrolithia- sis. Box 675.E. In suggested that an intratubular site of solid phase into the urinary space. the loop of Henle (Figure 1) with sub- with nephrolithiasis. Invest. ed heterogeneous nucleation and for- Over 65 years ago. that no conflict of interest exists. 6. doi:10. Bushinsky.1172/JCI200317423. the papillary tip. Glomerular-specific alter. um oxalate crystals adhered to cul. in the most severe ration with respect to calcium oxalate. serving as a nidus intestinal bypass. 7. Zhou. S.1172/JCI200318016. 2002. of trophoblast invasion: from normal implantation lar angiogenesis and renal arteriogenesis in mice. Maynard. C. Phone: (585) 275-3660. 5. 111:707–716. Clin. were common in for growth into larger. Vascular endothelial growth tions. and low platelets syndrome.. King. Part 1: clinical and pathophysiologic considera. Finlayson later argued that. Am. serving as a heterogeneous ment membrane of the thin limbs of quently form stones. University of Rochester School of Site of the initial solid phase (Figure 2). where supersaturated fluid awaits and formation of kidney stones. Howev. Surv. factor ligands and receptors that regulate human 3. They sampled metabolic abnormality of idiopathic oxalate. and Yagel. had neither plaque nor crystals.. 187:233–238. Nephrol. calculi.1172/JCI200317189. hypertension. and finally. et al. cient time for formation of a lumen. 111:649–658. genesis of stone formation and allow investigators to propose and test more Nephrolithiasis: site of the initial focused hypotheses. Erosion of this they also subsequently form stones. Am. absorb rapid flow of the renal ultrafiltrate then to the interstitial tissue sur- oxalate in excess leading to increased through the tubule.rochester. clinically signif. et al. Invest. plex. Semin. 9. Invest. 2003. 160:1405–1423. supersaturated with Strong Memorial Hospital. Yet until the ele- University of Rochester School of Medicine and Dentistry and the Nephrology Unit. Soc. A. the tubular respect to calcium oxalate. Anat. and pro. 4. gant study by A. Podjarny. J. E-mail: David_Bushinsky@urmc. 111:602–605 (2003). which is supersaturated with respect asis. S. obstructing solid phase (4). Other patients nucleation surface for calcium oxalate. elevated liver 23:2–13. other investigators found that calci... but these arose within the tubule lumens of terminal collecting ducts Address correspondence to: David A. crystals formed in the papillary inter. He nephrolithotomy. Obstet. 2002. J. subjected to nephrecto- Conflict of interest: The author has declared site of initial crystallization would my. doi:10. G. they urine calcium excretion and supersatu. J. where they mation of kidney stones. Baylis. may have Avenue. on the cell surface. who have had an B. Gynecol. improve understanding of the patho. 8. nary space. Perinatol. Endocrinol.