There is compelling evidence that the G-protein coupled receptor APJ and its cognate peptide ligand apelin constitute a signaling pathway employed by the endothelial cell to regulate numerous aspects of cardiovascular function and response to disease. 1) In the adult vasculature, circulating apelin binding APJ on endothelial cells decreases blood pressure in a nitric oxide-dependent fashion. 2) Endothelial cells in culture are stimulated by apelin to migrate and divide, and this stimulation is mediated in part by nitric oxide. 3) The differential expression of apelin mRNA levels in response to laminar shear stress, hypoxia, oxidative stress, and vascular disease suggests that apelin is involved in atherosclerosis or the vessel response to disease. 4) In the heart, apelin produced by coronary endothelial cells provides one of the most potent inotropic signals yet characterized for myocardial cells. We hypothesize that the apelin-APJ signaling pathway provides the endothelial cell a highly regulated mechanism for monitoring and adjusting cardiovascular homeostatic mechanisms, including a key adaptive response to injury in the vessel wall. Experiments proposed in this application will investigate salient features of the apelin-APJ signaling pathway in the vasculature, and how it interacts with the nitric oxide and angiotensin pathways to modulate disease processes. Primarily, experiments will focus on mouse genetic models designed to express no apelin (knockout mice) or express increased levels of apelin (human BAG transgenic mice) as well as tissue-restricted APJ knockout mice, and wild type mice with pharmacological modulation of signaling. The physiological role of pathway activation will be evaluated with three approaches. Comprehensive studies conducted on explanted vessels will directly examine the effects of apelin-APJ signaling on vascular tone and investigate underlying mechanisms for these effects; conductance catheter measurements will evaluate the in vivo inotropic effects of apelin and allow the discrimination of cardiac versus vascular effects in responses to manipulation of apelin expression level. The role of apelin and APJ in vascular pathophysiology will be evaluated with the apoE knockout model of atherosclerosis, and the carotid artery ligation model of vascular remodeling. In vivo studies will be complemented with targeted in vitro studies designed to elucidate fundamental cellular functions that are initiated in endothelial cells by this pathway. ? ?
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