Elevated Placental Soluble Vascular Endothelial Growth Factor Receptor-1 Inhibits Angiogenesis in Preeclampsia

Abstract

Abstract-Preeclampsia is an inflammatory disorder in which serum levels of vascular endothelial growth factor (VEGF) and its soluble receptor-1 (sVEGFR-1, also known as sFlt-1) are elevated. We hypothesize that VEGF and placenta growth factor (PlGF) are dysregulated in preeclampsia due to high levels of sVEGFR-1, which leads to impaired placental angiogenesis. Analysis of supernatants taken from preeclamptic placental villous explants showed a four-fold increase in sVEGFR-1 than normal pregnancies, suggesting that villous explants in vitro retain a hypoxia memory reflecting long-term fetal programming. The relative ratios of VEGF to sVEGFR-1 and PlGF to sVEGFR-1 released from explants decreased by 53% and 70%, respectively, in preeclampsia compared with normal pregnancies. Exposure of normal villous explants to hypoxia increased sVEGFR-1 release compared with tissue normoxia (PϽ0.001), as did stimulation with tumor necrosis factor-␣ (PϽ0.01). Conditioned medium (CM) from normal villous explants induced endothelial cell migration and in vitro tube formation, which were both attenuated by pre-incubation with exogenous sVEGFR-1 (PϽ0.001). In contrast, endothelial cells treated with preeclamptic CM showed substantially reduced angiogenesis compared with normal CM (PϽ0.001), which was not further decreased by the addition of exogenous sVEGFR-1, indicating a saturation of the soluble receptor. Removal of sVEGFR-1 by immunoprecipitation from preeclamptic CM significantly restored migration (PϽ0.001) and tube formation (PϽ0.001) to levels comparable to that induced by normal CM, demonstrating that elevated levels of sVEGFR-1 in preeclampsia are responsible for inhibiting angiogenesis. Our finding demonstrates the dysregulation of the VEGF/PlGF axis in preeclampsia and offers an entirely new therapeutic approach to its treatment.

Endothelium, Blood Vessels and Angiogenesis – A Workshop Report

“…When all measured ligands were considered within all groups of perfusate and serum samples, there was found to be a common inverse relationship between HAL author manuscript inserm-00175602, version 1 sVEGFR-1:tVEGF ratio and fVEGF levels. This relationship is in agreement with other studies on maternal serum [12,13].…”

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…VEGF‐A has been shown to stimulate the expression of sFlt‐1 by regulating the alternative splicing of the Flt‐1 gene94 in both in vascular endothelial cells and human placental explants 65, 95. VEGF‐A binds to the VEGFR2 receptor, and by protein kinase C (PKC)–MEK signaling, acts on the VEGF‐A Response Element on Intron 13 of the VEGFR1 gene 94.…”

Novel Angiogenic Factors for Predicting Preeclampsia: sFlt-1, PlGF, and Soluble Endoglin~!2008-08-29~!2008-12-15~!2009-01-02~!

“…sFlt-1 may play an important role in the pathogenesis of preeclampsia and may actually be the cause of the syndrome. Karumanchi and Epstein [23] had summarized 10 lines of accumulating evidence from their own as well as other investigators' findings, e.g., sFlt-1 antagonizes VEGF signalling; administration of sFlt-1, anti-VEGF antibodies or inhibitors to animals or cancer patients leads to preeclampsia like symptoms; and the endothelial dysfunction induced by preeclampsia can be reversed by removal of sFlt-1 or by addition of excess VEGF [24][25][26][27][28][29].…”