Abstract P613: The Effect of Metabolic Factors on Hypoxia-Induced sFlt-1 Secretion in Rat Placental Villi

Abstract

Although the etiology of preeclampsia (PE) remains unclear, evidence indicates that impaired trophoblast invasion followed by placental ischemia/hypoxia promotes the release of placental anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1), into the maternal circulation. sFlt-1 blocks the pro-angiogenic actions of vascular endothelial growth factor to elicit maternal endothelial dysfunction and ultimately hypertension. Obesity is a major risk factor for PE. In addition, increased circulating metabolic factors, such as leptin and insulin have been associated with PE. However, the mechanisms whereby obesity and its related metabolic factors increase the risk for the development of PE are unknown. The aim of this study was to evaluate whether chronic leptin or insulin exposure exacerbate hypoxia-induced sFlt-1 secretion from rat placental villi. In order to address this question, placental villous explants were isolated from placentas of normal pregnant rats (n=4, 3 placentas per rat) and pregnant rats treated with either leptin (0.5 mg/kg/min i.p.; n=3, 3 placentas per rat) or insulin (1.5 mU/kg/min s.c.) supplemented with 20% glucose in drinking water (n=3, 3 placentas per rat) from gestational day 14 to 19. Placental explants were then incubated for 48 h at 37 °C under normoxia (6% O2) or hypoxia (1% O2) and sFlt-1 secretion in cultured media was measured by ELISA. While hypoxia significantly enhanced sFlt-1 release of explants from normal pregnant rats compared with normoxia (3224±224 vs 4251±236 pg/mg; P<0.05), explants from chronic hyperleptinemic (3197±178 vs. 3762±317 pg/mg) or euglycemic hyperinsulinemic (4066±186 vs. 4251±213 pg/mg) pregnant rats secreted similar sFlt-1 levels under normoxic and hypoxic conditions, respectively. Additionally, chronic leptin or insulin treatments did not exacerbate the effect of hypoxia on sFlt-1 release. In conclusion, our in vitro studies with placental villi from chronic hyperleptinemic or euglycemic hyperinsulinemic pregnant rats showed no exacerbation of hypoxia-induced sFlt-1 secretion.