The goal of our research is to elucidate the role of atrial natriuretic peptide (ANP) and ANP receptors in hypoxia-induced pulmonary hypertension. The general hypothesis of the current proposal is that, under hypoxic conditions, ANP gene expression is enhanced, and ANP clearance receptor (NPR-C) gene expression is downregulated in lung and thereby, circulating ANP is elevated. We further hypothesize that the enhanced circulating ANP has protective effects against the development of hypoxia-induced pulmonary hypertension. Studies completed during the current funding period demonstrated that ANP attenuates the development of hypoxia-induced pulmonary hypertension and vascular remodeling, and that ANP gene expression and secretion in the heart and in cultured atrial myocytes are enhanced during hypoxic exposure. We have also demonstrated that the expression NPR-C, but not the biologically active NPR-A or NPR-B receptors, is suppressed in lung of hypoxia-adapted rats and transgenic mice with homologous deletion of the ANP gene (ANP-null mice). Further, we have demonstrated that the hypoxia-responsive growth factors FGF-1 and -2 and PDGF-BB, but not hypoxia per se, inhibit NPR-C expression in smooth muscle cells derived from main pulmonary arteries of rats. Together with our earlier finding that administration of a peptide agonist of NPR-C was associated with increased circulating ANP levels and reduced pulmonary artery pressure in hypoxia-adapted rats, these data define roles for 1) NPR-C as a regulator of endogenous ANP levels, and 2) ANP as a modulator hormone that protects against the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxic pulmonary hypertension and vascular remodeling. Studies described in the current application will focus on the cellular and molecular mechanisms of hypoxia-responsive growth factor-induced alterations in NPR-C gene expression.
The Specific Aims of the current proposal are: 1) To test the hypotheses that expression of FGF and PDGF is increased, in association with reduced expression of NPR-C, in the pulmonary microcirculation (resistance vessels) under hypoxic condition and that this downregulation of NPR-C is independent of endogenous ANP expression. 2) To define the intracellular signaling mechanisms leading to downregulation of NPR-C gene expression by hypoxia-responsive growth factors FGF-1 and PDGF-BB in cultured pulmonary microvascular smooth muscle cells (PMVSMCs). 3) To elucidate the mechanisms of transcriptional and/or posttranscriptional regulation of NPR-C gene expression by FGF-1 and PDGF-BB, and to characterize the cis-and trans-acting factors required for NPR-C gene expression. Sprague-Dawley rats, ANP-null mice, and cultured PMVSMCs will be studied in these experiments.
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