title: Regulation of soluble fms-like tyrosine kinase-1 production in response to placental ischemia/hypoxia: role of angiotensin II.
abstract: While soluble fms-like tyrosine-1 (sFlt-1) is implicated in the pathogenesis of hypertension during preeclampsia, the mechanisms leading to the enhanced sFlt-1 production remain unclear. A recent report suggests exogenous angiotensin II (ANGII) stimulates sFlt-1 production in pregnant rats, however, the role of endogenous ANGII in mediating the placental production of sFlt-1 in response to placental ischemia remains unknown. Therefore, the purpose of this study was to determine the role of endogenous ANGII in mediating the placental production of sFlt-1 in response to placental ischemia in pregnant Sprague-Dawley rats. To this end we compared sFlt-1 and ANGII levels from placental explants collected from normal pregnant (NP) and Reduced Uterine Perfusion Pressure (RUPP) rats. sFlt-1 (3271 ± 264 vs. 2228 ± 324 pg/mL, P < 0.05) and ANGII levels (43.2 ± 2.8 vs. 26.7 ± 1.9 pg/mL, P < 0.05) were higher in placental explants from RUPP rats versus NP rats. Administration of Losartan, an angiotensin type 1 (AT1) receptor antagonist, (10 mg/day for 5 days) to RUPP rats significantly reduced plasma levels of sFlt-1 (1432 ± 255 pg/mL, P < 0.05) when compared with untreated control rats (3431 ± 454 pg/mL). In addition, RUPP-induced hypertension was significantly reduced (113 ± 2 mmHg vs. 139 ± 2 mmHg, P < 0.05). In conclusion, placental sFlt-1 and ANGII production are significantly elevated in response to placental ischemia in pregnant rats. In addition, AT1 receptor activation, by endogenous ANGII, appears to play an important role in mediating the placental production of sFlt-1 in response to placental ischemia in pregnant rats.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Murphy
authors.affiliation: Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Kathy
authors.initials: K
authors.lastname: Cockrell
keywords: Angiotension II; placental ischemia; preeclampsia; reduced uterine perfusion pressure; sFlt‐1