Insulin-like growth factors and placental ischemia-induced hypertension in the pregnant rat.

Abstract

Preeclampsia is a gestational condition characterized by new onset hypertension and proteinuria and often results in fetal growth restriction. This pregnancy-specific condition occurs in ~8 percent of live birth pregnancies and is the leading cause of maternal and neonatal mortality and morbidity. Delivery is the primary therapeutic approach for preeclampsia; hence, the long-term goal of preeclampsia research is to determine what causes preeclampsia and to find treatments to alleviate maternal hypertension and extend pregnancy to improve fetal outcome. Chronic placental ischemia via the reduced uteroplacental perfusion pressure (RUPP) model, utilized in this project to mimic the preeclamptic condition during the third trimester in the pregnant rat, results in hypertension, intrauterine growth restriction and fetal loss. Insulin-like Growth Factors (IGF-1 and IGF-2) have been reported to play an important role in fetal development, and low plasma levels of IGF-1 have been associated with reduced endothelial function and have been closely linked with elevated blood pressure in non-pregnant subjects. The hypotheses tested in this project are that 1) placental ischemia induced by RUPP decreases circulating and placental levels of IGF-1 and IGF-2; and 2) administering exogenous IGF-1 in RUPP rats attenuates maternal hypertension, endothelial dysfunction, intrauterine growth restriction and fetal loss. The data show that chronic placental ischemia decreases circulating IGF-2 levels, but does not affect circulating IGF-1 or placental IGF-1, IGF-2 and IGF-1 receptor levels. Further, administering exogenous IGF-1 in RUPP rats during the third trimester attenuates blood pressure and decreases fetal loss, but does not improve endothelial function or fetal weight. Overall, these studies determined that the mechanisms that regulate IGF signaling are potential targets for improved therapies for treating maternal blood pressure in preeclampsia and gestational hypertension.