Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1

Melissa Cudmore, Shakil Ahmad, Bahjat Al-Ani, Takeshi Fujisawa, H Coxall, K Chudasama, LR Devey, SJ Wigmore, A Abbas, Peter Hewett, Asif Ahmed

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304 Citations (Scopus)


Background-Preeclampsia is characterized clinically by hypertension and proteinuria. Soluble Flt-1 (sFlt-1; also known as soluble vascular endothelial growth factor receptor-1 [VEGFR-1]) and soluble endoglin (sEng) are elevated in preeclampsia, and their administration to pregnant rats elicits preeclampsia-like symptoms. Heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli. Thus, we hypothesized that HO-1 upregulation may offer protection against preeclampsia by inhibiting sFlt-1 and sEng release. Methods and Results-Preeclamptic villous explants secreted high levels of sFlt-1 and sEng. Adenoviral overexpression of HO-1 in endothelial cells inhibited VEGF-mediated sFlt-1 release and interferon-gamma-and tumor necrosis factor-alpha-induced sEng release, whereas HO-1 inhibition potentiated sFlt-1 and sEng production from endothelial cells and placental villous explants. Consistent with these findings, mice lacking HO-1 produced higher levels of sFlt-1 and sEng compared with wild-type mice. Using selective ligands (VEGF-E and placental growth factor) and a receptor-specific inhibitor (SU-1498), we demonstrated that VEGF-induced sFlt-1 release was VEGFR-2 dependent. Furthermore, CO-releasing molecule-2 (CORM-2) or CO decreased sFlt-1 release and inhibited VEGFR-2 phosphorylation. Treatment of endothelial cells with statins upregulated HO-1 and inhibited the release of sFlt-1, whereas vitamins C and E had no effect. Conclusions-The present study demonstrates that the HO-1/CO pathway inhibits sFlt-1 and sEng release, providing compelling evidence for a protective role of HO-1 in pregnancy, and identifies HO-1 as a novel target for the treatment of preeclampsia.
Original languageEnglish
Pages (from-to)1789-97
Number of pages9
Early online date19 Mar 2007
Publication statusPublished - 19 Mar 2007


  • endothelium
  • endothelium-derived factors
  • pregnancy
  • statins
  • heme oxygenase-1
  • angiogenesis
  • preeclampsia


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