description): Intrauterine growth restriction (IUGR) occurs in 4 to 7% of all infants delivered in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is fundamental to most cases of IUGR in humans. Endothelin-1 (ET-1) and nitric oxide (NO) are vascular mediators which are important for the regulation of uterine and placental vascular tone. The investigators hypothesize that increased endogenous ET-1, a locally active vasoconstrictor, is critically important in the pathophysiology of IUGR. They will evaluate the molecular mechanisms regulating the activities of both ET-1 and NO in uteroplacental perfusion and IUGR. They also will evaluate the role of endogenous ET-1 in the pathophysiology of IUGR, using ET-1 receptor antagonists. The investigators will use two different animal models of IUGR which were selected because of the opportunity they provide to study the roles of these two mediators. 1) Chronic maternal hypoxia is a model of IUGR which is associated with increased endogenous ET-1 as well as decreased nitric oxide synthase (NOS) activity. This model will be used to evaluate the efficacy of ET-1 antagonists to improve uteroplacental perfusion and prevent IUGR. 2) Chronic NOS inhibition is another established model of IUGR which also is associated with increased circulating endogenous ET-1. Additionally, NOS inhibition in the rat mimics human preeclampsia, a condition commonly associated with IUGR. The investigators will use this model to evaluate whether ET-1 antagonism prevents the preeclampsia-like state, as well as IUGR, caused by chronic NOS inhibition. In each of these models, they will evaluate the molecular mechanisms which regulate ET-1 activity. Additionally, in the hypoxia model the investigators will evaluate the molecular mechanisms regulating NO activity. The goal is to better understand the regulation of uteroplacental perfusion, to delineate the molecular mechanisms regulating the synthesis and activity of ET-1 and NO, and, using ET-1 antagonists, to evaluate the specific role of ET-1 in the pathophysiology of IUGR.
| Neerhof, Mark G; Jilling, Tamas; Synowiec, Sylvia et al. (2008) Altered endothelin receptor binding in response to nitric oxide synthase inhibition in the pregnant rat. Reprod Sci 15:366-73 |
| Thaete, Larry G; Jilling, Tamas; Synowiec, Sylvia et al. (2007) Expression of endothelin 1 and its receptors in the hypoxic pregnant rat. Biol Reprod 77:526-32 |
| Thaete, L G; Kushner, D M; Dewey, E R et al. (2005) Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction. Placenta 26:242-50 |
| Thaete, Larry G; Dewey, Elizabeth R; Neerhof, Mark G (2004) Endothelin and the regulation of uterine and placental perfusion in hypoxia-induced fetal growth restriction. J Soc Gynecol Investig 11:16-21 |
