Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia

Ahmad, Shakil and Ahmed, Asif (2004). Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circulation Research, 95 (9), pp. 884-891.

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-1and 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 (P<0.001), as did stimulation with tumor necrosis factor-α (P<0.01). 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 (P<0.001). In contrast, endothelial cells treated with preeclamptic CM showed substantially reduced angiogenesis compared withnormal CM (P<0.001), 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 (P<0.001) and tube formation (P<0.001) 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 preeclampsiaand offers an entirely new therapeutic approach to its treatment.

Publication DOI: https://doi.org/10.1161/01.RES.0000147365.86159.f5
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Aston Medical School
Uncontrolled Keywords: angiogenesis,sFlt-1,VEGF,PLGF,preeclampsia
Full Text Link: http://circres. ... ontent/95/9/884
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Published Date: 2004-10-07
Authors: Ahmad, Shakil ( 0000-0002-9294-0475)
Ahmed, Asif

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