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

Abstract

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...

Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia

“…In the current study, we found that IL-17 inhibition normalized sFlt-1 and partially restored circulating levels of VEGF in RUPP recipients. This is another mechanism that may contribute to the improved maternal and fetal outcomes as VEGF supplementation has been shown to ameliorate PE pathophysiology in animal models and is being considered as a potential therapeutic option for PE women (2,16,39,48,86). Together, these data indicate that the improvement in maternal blood pressure and fetal growth following IL-17RC infusion can be partially attributed to the decrease in cNK cell activation and the resultant reduction in inflammatory cytokines and increase in VEGF levels.…”

“…The angiogenic imbalance between s-Flt1 and VEGF has also been identified as a significant contributor to PE (48). Increased levels of sFlt-1 and decreased levels of circulating VEGF have been observed in PE women and animal models when compared with their normal pregnant counterparts (1,48,58,61).…”

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

“…We read with great interest the comments to our article 1 by Jha et al 2 regarding the role of vascular endothelial growth factor (VEGF) and sVEGFR-2 in pre-eclampsia (PE). We agree with the observations made by Jha et al that our data (with respect to VEGF) seem only apparently dramatically opposite and we would like to provide our view to explain these differences in the results and their interpretation.…”