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-␥-and tumor necrosis factor-␣-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. Key Words: endothelium Ⅲ endothelium-derived factors Ⅲ heme oxygenase-1 Ⅲ preeclampsia Ⅲ pregnancy Ⅲ statins Ⅲ angiogenesis C ardiovascular disease and preeclampsia share some common risk factors, such as insulin resistance, obesity, diabetes mellitus, and inflammation. 1,2 The disruption of endothelial homeostasis and inflammation are fundamental to the initiation and progression of atherosclerosis 3 and preeclampsia. 4 Preeclampsia is a maternal systemic endothelial disease defined clinically as hypertension and proteinuria after 20 weeks' gestation that affects 3% to 8% of all pregnancies and women.5 Women with a history of preeclampsia and their offspring are at greater risk of developing cardiovascular disease later in life. 6,7 Clinical Perspective p 1797Preeclampsia involves dysregulated placental angiogenesis, 8 resulting in the release of soluble antiangiogenic factors that induce systemic endothelial dysfunction. 9 Two key antiangiogenic circulating factors that give the highest strength of association with preeclamptic outcome are soluble Flt-1 (sFlt-1) and soluble endoglin (sEng). 10 -12 Maternal serum levels of sFlt-1 are elevated 5 weeks before the clinical onset of preeclampsia. 10,13-16 sEng, a placenta-derived 65-kDa cleaved form of endoglin (also known as CD105), a coreceptor for transform...

Abstract-Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose-and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system. (Circ Res. 2007;100:88-95.)

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