The goal of this research is elucidate the role of endothelin-1 (ET-1) and ET receptors in hypoxia-induced pulmonary hypertension. Results of studies over the last 4 years have confirmed the hypothesis that ET-1 gene expression and ET-1 synthesis are selectively enhanced in lungs of rats exposed to hypoxia. Moreover, studies have confirmed that gene expression of the ET-1 receptors, ET-A and ET-B, is concomitantly enhanced in lungs of these animals. Hypoxia-induced upregulation of ET-1, ET-A and ET-B gene expression and ET-1 release have all paralleled functional and histopathologic evidence of the development of pulmonary hypertension. It is believed that ET-1, generated in conditions of hypoxia, acts via a paracrine mechanism on pulmonary ET-A receptors and, through its interaction, plays a fundamental etiologic role in hypoxia-induced pulmonary vasoconstriction, vascular remodelling, and maintenance of chronic pulmonary hypertension. Recently these investigators have demonstrated that selective ET-A receptor antagonists and a combined ET-A+ET-B receptor antagonist can both prevent and reverse acute and chronic hypoxia-induced pulmonary vasoconstriction and pulmonary hypertension. These data define a role for ET-1 as an important mediator of hypoxia-induced pulmonary hypertension.
The specific aims of the current proposal are: 1) To test the hypothesis that ET-1 contributes to acute and chronic hemodynamic and structural adaptations to hypoxia in the rat by activating both ET-A and ET-B receptors. 2) To determine the cellular sites of ET-1 and ET-A and ET-B receptor gene expression under control conditions and in response to hypoxia. 3) To define the cis-regulatory element(s) in the 5' flanking region of the ET-1 gene involved in amplifying transcription of the ET-1 gene during exposure to hypoxia. 4) To identify and characterize the hypoxia-responsive transcription factor protein(s) that regulate ET-1 gene expression in response to hypoxia. Sprague-Dawley rats exposed to hypoxia (10 percent O2 at 1 atm.) or room air will be studies for Specific Aims 1 and 2. Transgenic mice harboring a human prepro-ET-1 promoter/luciferase reporter gene will be studied in Specific Aim 2. Cultured endothelial and smooth muscle cells derived from human and rat pulmonary microvessels and systemic vascular beds will be studied in Specific Aims 3 and 4.
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