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

• Published in: Circulation (New York, N.Y.) Vol. 115; no. 13; pp. 1789 - 1797
• Main Authors: CUDMORE, Melissa, AHMAD, Shakil, AHMED, Asif, AL-ANI, Bahjat, FUJISAWA, Takeshi, COXALL, Heather, CHUDASAMA, Kunal, DEVEY, Luke R, WIGMORE, Stephen J, ABBAS, Allyah, HEWETT, Peter W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 03.04.2007
• Subjects: Animals; Antigens, CD - physiology; Antioxidants - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Carbon Monoxide - pharmacology; Cardiology. Vascular system; Cell Hypoxia; Cells, Cultured - drug effects; Culture Media, Serum-Free - pharmacology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endoglin; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Female; Genetic Vectors; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - physiology; Heme Oxygenase-1 - deficiency; Heme Oxygenase-1 - physiology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Interferon-gamma - pharmacology; Medical sciences; Mice; Mice, Knockout; Organ Culture Techniques; Organometallic Compounds - pharmacology; Oxidative Stress; Placenta - pathology; Placenta Growth Factor; Pre-Eclampsia - metabolism; Pre-Eclampsia - pathology; Pregnancy; Pregnancy Proteins - pharmacology; Rats; Receptors, Cell Surface - physiology; Recombinant Fusion Proteins - physiology; RNA, Small Interfering - pharmacology; Solubility; Swine; Tumor Necrosis Factor-alpha - pharmacology; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - physiology; Vascular Endothelial Growth Factor Receptor-2 - physiology; Pregnancy disorders; Enzyme; Preeclampsia; pregnancy; Heme oxygenase (decyclizing); Cardiovascular disease; Oxidoreductases; Pregnancy toxemia; endothelium endothelium-derived factors heme oxygenase-1 preeclampsia; Endothelium
• DOI: 10.1161/CIRCULATIONAHA.106.660134
• ISSN: 0009-7322

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. 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. 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.