Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia.
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 (P<0.001), as did stimulation with tumor necrosis factor-alpha (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 with normal 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 preeclampsia and offers an entirely new therapeutic approach to its treatment.
Ahmad
Shakil
S
Department of Reproductive and Vascular Biology, The Medical School, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TG, UK. a.s.ahmed@bham.ac.uk
Ahmed
Asif
A
D017398:Alternative Splicing; D000818:Animals; D001011:Aorta / Q000166:cytology; D015687:Cell Hypoxia; D002478:Cells, Cultured / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D002824:Chorionic Villi / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood* / Q000503:physiopathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000502:physiology; D012995:Solubility; D034421:Sus scrofa; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000235:genetics / Q000502:physiology*
D017077:Culture Media, Conditioned; C000608036:PGF protein, human; D010446:Peptide Fragments; D011257:Pregnancy Proteins; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D010100:Oxygen