The hypothesis is that ET-1 is a critically important regulator of placental perfusion, and thus fetal growth and pregnancy outcome. The investigator will evaluate the molecular mechanisms regulating the activities of both ET-1 and NO in uteroplacental perfusion and IUGR. The investigator will also evaluate the role of endogenous ET-1 in the pathophysiology of IUGR using an ET-1 receptor antagonist.
Aim 1 is to evaluate the role of ET-1 in the pathophysiology of IUGR.
Aim 2 is to investigate the molecular mechanisms regulating ET-1 and NO in the pathophysiology of IUGR.
In Aim 1, the investigator will evaluate the effects of an ETA on fetal and placental weight (Exp 1), uteroplacental blood flow measured with radioactive microspheres (Exp 2), maternal hypertension and proteinuria (Exp 3), and placental necrosis (Exp 4) of rats treated with a NOS inhibitor.
In Aim 2, the expression of ET-1 peptide, ET-1 mRNA, ETA and ETB receptor mRNA and binding sites, endothelin converting enzyme, and NOS activity and protein mass will be measured in rats exposed to hypoxia and to NOS inhibition. Cellular localization of ET, ET receptors, and NOS isoforms will be performed with immunocytochemistry.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Human Embryology and Development Subcommittee 1 (HED)
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Evanston Hospital
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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
Thaete, L G; Neerhof, M G; Silver, R K (2001) Differential effects of endothelin A and B receptor antagonism on fetal growth in normal and nitric oxide-deficient rats. J Soc Gynecol Investig 8:18-23
Madsen, K M; Neerhof, M G; Wessale, J L et al. (2001) Influence of ET(B) receptor antagonism on pregnancy outcome in rats. J Soc Gynecol Investig 8:239-44
Thaete, L G; Neerhof, M G (2000) Endothelin and blood pressure regulation in the female rat: studies in normal pregnancy and with nitric oxide synthase inhibition-induced hypertension. Hypertens Pregnancy 19:233-47