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Expression of Endothelin 1 and Its Receptors in the Hypoxic Pregnant Rat¹

Departments of Obstetrics and Gynecology³ and Northwestern University Feinberg School of Medicine,⁵ Chicago, Illinois 60611 Pediatrics,⁴ Evanston Northwestern Healthcare, Evanston, Illinois 60201

ABSTRACT

Endothelin 1 (EDN1) plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction in the rat. In this study we evaluated the effects of chronic maternal hypoxia on the expression of endothelin and its receptors and on receptor binding activity in the uterus and placenta of the rat, in order to elucidate their roles in hypoxia-induced fetal growth restriction. Timed-pregnant Sprague-Dawley rats were maintained in either a normoxic or a normobaric hypoxic (12% O₂) atmosphere from Gestational Days 18–21. Uterine and placental tissues collected on Gestational Day 21 were assayed for Edn1, Ednra, and Ednrb (endothelin receptors) mRNA expression by real-time quantitative RT-PCR, for localization of EDN1 and its receptors by immunohistochemistry, for EDNRA and EDNRB protein expression by Western blot, and for receptor binding activity by homologous competitive binding assays. EDN1 mRNA expression was significantly increased in the hypoxic placenta, but not in the uterus, compared with normoxic controls. Immunohistochemistry revealed increased EDN1 specifically in the labyrinth of the placenta. Receptor mRNA levels were not significantly affected by hypoxia, but EDNRA protein expression was significantly decreased specifically in the uterine placental beds. Receptor binding decreased significantly in response to hypoxia in all tissues investigated, compared with controls. These results suggest that chronic maternal hypoxia results in increased expression of EDN1 in the placenta but not in the uterus, and that reduced binding activity, rather than regulation of receptor expression, is a mechanism by which these tissues regulate the local hemodynamic response to increased endogenous placental EDN1 in the setting of hypoxia.

environment, placenta, pregnancy, uterus

¹Supported by National Institutes of Health grants HD34777 and HD01484 (L.T.).

Correspondence: ²Larry G. Thaete, Evanston Northwestern Healthcare, 2650 Ridge Ave., Suite 1507 Walgreen, Evanston, IL 60201. FAX: 847 570 2910; e-mail: Lthaete{at}enh.org

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