Published online before print December 7, 2006, doi: 10.1161/01.RES.0000254703.11154.18
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Submitted on December 5, 2005
Revised on November 21, 2006
Accepted on November 28, 2006
Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy
Cissy Chenyi Zhou ;
From the Department of Biochemistry & Molecular Biology (C.C.Z., T.M., L.X., S. Abbasi, C.X.S., R.E.K., Y.X.), University of Texas at Houston Medical School; Department of Reproductive and Vascular Biology (S. Ahmad, P.W.H., A.A.), Institute for Biomedical Research, The Medical School, University of Birmingham, Edgbaston, UK; and Birmingham Women’s Hospital (S. Ahmad, P.W.H., A.A.), Edgbaston, UK.
* To whom correspondence should be addressed. E-mail: yang.xia{at}uth.tmc.edu.
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.
Key words: sFlt-1 • angiotensin II • AT1 receptor • pregnancy • placenta • calcineurin.
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