Overexpression of the Soluble Vascular Endothelial Growth Factor Receptor in Preeclamptic Patients: Pathophysiological Consequences

Tsatsaris, Vassilis; Goffin, Frédéric; Munaut, Carine; Brichant, Jean-François; Pignon, Marie-Rose; Noël, Agnès; Schaaps, Jean-Pierre; Cabrol, D.; Frankenne, Françis; Foidart, Jean‐Michel

doi:10.1210/jc.2003-030528

Cited by 428 publications

(333 citation statements)

References 51 publications

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“…This is contrary to what has been noted in almost all published reports that show reduced VEGF levels. [2][3][4][5] In our investigations, we have consistently found circulating VEGF levels to be undetectable in PE/eclampsia. The basis for this reduction is also well defined.…”

supporting

confidence: 62%

Angiogenic balance and diagnosis of pre-eclampsia: selecting the right VEGF receptor

et al. 2011

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We read with interest the report by Rath and Tripathi 1 in which they have evaluated the levels of serum vascular endothelial growth factor (VEGF) and soluble VEFR receptor type 2 in hypertensive disorders of pregnancy. Their findings are certainly intriguing. First, they found increased VEGF levels in pre-eclampsia (PE) and eclampsia. This is contrary to what has been noted in almost all published reports that show reduced VEGF levels. [2][3][4][5] In our investigations, we have consistently found circulating VEGF levels to be undetectable in PE/eclampsia. The basis for this reduction is also well defined. There is ample evidence to prove that circulating VEGF as well as placental growth factor (PlGF) are bound to the excess soluble fms-like tyrosine kinase-1 (sFlt-1) or sVEGFR-1 that is produced by the preeclamptic placenta. 2 There is a close relationship between the elevated sFlt-1 and the reduction in VEGF and PlGF. The authors have not discussed this major difference between published reports and their findings. It is unclear whether the kit used in their study measured free or total (free as well as that bound to sFLt-1) VEGF. If it measures both forms of VEGF, then the total levels could be elevated. 3 This distinction is critical, however, as it is only the free VEGF that is biologically available. Interestingly, their explanation of the reduced sVEGRF2 level is based on the premise that this reflects receptor downregulation as a result of excess VEGF.Also of interest is their decision to evaluate sVEGFR2 as a diagnostic marker. The hypothesis behind the utility of this molecule as a diagnostic marker is unclear. In contrast the biological basis behind alterations in sFlt-1 in PE has been well studied. A large number of studies, both experimental and human, have shown consistent increases in sFlt-1 in PE, and have suggested using it either alone or in combination with serum PlGF (as sFlt-1:PlGF ratio) to differentiate PE from other hypertensive disorders of pregnancy. 2,5,6 Several studies have shown that these possess superior discriminatory ability than that shown by the authors. 5,7,8 In a comparative study of pre-eclamptic and normotensive pregnancies, we found the circulating sFlt-1 to be significantly increased in PE compared with normotensive pregnancies, 9 whereas the mean PlGF levels were reduced. Receiver operating characteristic curve analysis showed that sFlt-1 and sFlt-1:PlGF ratio cutoffs of 15.7 and 92.2 ng ml À1 , respectively, were able to distinguish PE from normotensive pregnancies with 100% sensitivity and specificity. PlGF alone had a slightly lower performance (cutoff 177.1 pg ml À1 ; AUC ¼ 98.3%; 95% CI 96.9-99.7).Apart from the fact that the findings are difficult to understand, some conclusions made in the paper seem to be overinterpretation of findings. These include suggestions of a 'role' for sVEGFR2 in the pathogenesis of PE, and that sVEGFR2 reflects endothelial health or endothelial progenitor cell regenerative ability. It is difficult to find the biological significance o...

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confidence: 62%

Angiogenic balance and diagnosis of pre-eclampsia: selecting the right VEGF receptor

et al. 2011

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“…Therefore, it is of interest to understand whether dysregulation in the VEGF family may be associated with preeclampsia and IUGR. Recent studies show evidence for a significant deregulation of the expression of VEGF, PlGF and their receptors in the placenta of severe early onset preeclampsia or IUGR [19].…”

Section: Expression Of Vegf Plgf and Their Receptors In Pregnancies mentioning

confidence: 99%

“…VEGF-A, PlGF and VEGFR-1 that are produced by villous and extravillous trophoblast cells are significantly upregulated in placentas from preeclamptic women and from cases with IUGR [19,20]. It seems that during pregnancy most of the circulating VEGF is bound to sVEGFR-1 produced in high amounts by the placenta [19][20][21].…”

Section: Expression Of Vegf Plgf and Their Receptors In Pregnancies mentioning

confidence: 99%

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Fetal growth restriction: a workshop report

et al. 2004

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Intrauterine growth restriction (IUGR) is associated with significantly increased perinatal morbidity and mortality as well as cardiovascular disease and glucose intolerance in adult life. A number of disorders from genetic to metabolic, vascular, coagulative, autoimmune, as well as infectious, can influence fetal growth by damaging the placenta, leading to IUGR as a result of many possible fetal, placental and maternal disorders. Strict definitions of IUGR and of its severity are needed in order to eventually distinguish among different phenotypes, such as gestational age at onset, degree of growth restriction and presence of hypoxia.This report explores and reviews some of the most recent developments in both clinical and basic research on intrauterine growth restriction, by seeking mechanisms that involve genetic factors, utero-placental nutrient availability and vascular growth factors.New exciting findings on the genomic imprinting defects potentially associated with IUGR, and the placental anomalies associated with the decreased nutrient transport are summarized. Moreover, recent data on angiogenic growth factors as well as new information arising from application of gene chip technologies are discussed.

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“…6,7 Elevations in circulating sFlt-1 and sEng and reduction in PlGF levels antedate the appearance of PE. [8][9][10][11] This suggests that perturbation of other pathways may be necessary for the development of clinical manifestations. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide secreted by endothelial and vascular smooth muscle cells.…”

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confidence: 99%

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

et al. 2011

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Placental overproduction of anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) has a key role in the development of preeclampsia (PE). Circulating endothelin-1 (ET-1) levels are also elevated in PE. In this study, we investigated the correlation between ET-1 and sFlt-1, placental growth factor (PlGF), sEng levels during uncomplicated normotensive pregnancy and PE. A total of 218 pregnant primigravid women were enrolled: 110 with PE and 108 uncomplicated normotensive pregnancies. PE was defined as new onset of elevated blood pressure (BP) 4140/90 mm Hg and X2 þ proteinuria on two occasions after 20 weeks of gestation in previously normotensive pregnant women. Circulating ET-1, sFlt-1, sEng and PlGF levels were estimated using enzyme immunoassays, and correlation between variables was ascertained. Women with PE showed higher levels of sFlt-1 (41.5 ± 15.7 vs 6.15 ± 3.4 ng ml -1 , Po0.001), sEng (84.9 ± 38.8 vs 13.2 ± 6.3 ng ml -1 , Po0.001), ET-1 (1.52 ± 0.55 vs 0.88±0.35 pg ml -1 , Po0.001) and sFlt-1:PlGF ratio (591.1±468.4 vs 18.3±2.1, Po0.001); and lower levels of PlGF (96.3 ± 47.2 vs 497.6 ± 328.2pg ml -1 , Po0.001). BP levels showed an independent relationship with sFlt-1:PlGF ratio in normotensive pregnant women and with sFlt-1:PlGF ratio and ET-1 in PE. sFlt-1 and sFlt-1:PlGF ratio correlated with proteinuria. ET-1 correlated significantly with sFlt-1, sEng and sFlt-1:PlGF ratio in PE. Our results show an association between elevation of sFlt-1 and sEng and ET-1 in the maternal circulation in PE, and strengthen the possibility that ET-1 may be a mediator in genesis of PE syndrome secondary to anti-angiogenic factors released by the placenta.

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Overexpression of the Soluble Vascular Endothelial Growth Factor Receptor in Preeclamptic Patients: Pathophysiological Consequences

Cited by 428 publications

References 51 publications

Angiogenic balance and diagnosis of pre-eclampsia: selecting the right VEGF receptor

Angiogenic balance and diagnosis of pre-eclampsia: selecting the right VEGF receptor

Fetal growth restriction: a workshop report

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

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