title: Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy.
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.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Texas-Houston Medical School, 6431 Fannin, MSB 6.200 Houston, TX 77030, USA.
authors.forename: Cissy Chenyi
authors.initials: CC
authors.lastname: Zhou
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: TieJuan
authors.initials: T
authors.lastname: Mi
authors.forename: Lingwei
authors.initials: L
authors.lastname: Xia
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Abbasi
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hewett
authors.forename: ChunXiao
authors.initials: C
authors.lastname: Sun
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D002824:Chorionic Villi / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014327:Trophoblasts / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D019703:Calcineurin