Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy


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.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences
Additional Information: © 2007 American Heart Association, Inc
Uncontrolled Keywords: sFlt-1 ,angiotensin II ,AT1 receptor ,pregnancy ,placenta,calcineurin
Publication ISSN: 1524-4571
Last Modified: 29 Mar 2024 08:10
Date Deposited: 06 Oct 2014 10:45
Full Text Link:
Related URLs: http://circres. ... ontent/100/1/88 (Publisher URL)
PURE Output Type: Article
Published Date: 2007
Published Online Date: 2006-12-07
Authors: Zhou, Cissy Chenyi
Ahmad, Shakil (ORCID Profile 0000-0002-9294-0475)
Mi, TieJuan
Xia, Lingwei
Abbasi, Shahrzad
Hewett, Peter W.
Sun, ChunXiao
Ahmed, Asif (ORCID Profile 0000-0002-8755-8546)
Kellems, Rodney E.
Xia, Yang



Version: Accepted Version

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