Alpha-Adrenoceptors in Vascular Wall Growth

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Alpha-1-adrenergic receptor (alpha 1A.R) activation by norepinephrine (NE) induces growth of smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs) in cell culture. Although alpha1AR stimulation has been proposed to contribute to hypertensive wall hypertrophy and fibrosis, exacerbate atherosclerosis, and to worsen restenosis after angioplasty, until our studies there was no in vivo evidence that this was from a direct effect because of absence of local drug delivery systems that could prevent confounding systemic hemodynamic actions. We have devised a novel method that overcomes this problem. This, together with a unique organ culture method, selective alpha1AR subtype antagonists, and knockout mice devoid of catecholamine synthesis or specific alpha1AR subtypes, will be used to investigate the hvnothesis that stimulation of a snecific allpha1AR subtvne on SMCs and AFBs contribute importantlv to intimal lesion growth, fibrosis and vascular remodeling. Our previous and preliminary results have demonstrated that specific al AR subtypes mediate growth of SMCs and AFBs in vitro and in vivo, and strongly contribute to restenosis after angioplasty, outward hypertrophic remodeling and the vascular hypertrophy and lumen loss that causes pulmonary hypertension. Aim I will complete the work in these models, and extend it to hypertensive wall hypertrophy. Aim II will determine how NE exacerbates wall growth by in vivo examination of proliferation, apoptosis, and migration with immunohistochemistry and western blot. Aim III will test the hypothesis that injury induces neurite outgrowth and increased NE content and/or release. Aim IV will identify the intracellular kinase pathway mediating NE?s trophic activity and test the hypothesis that it proceeds through reactive oxygen species-and/or EGF-receptor transactivation-dependent pathways. These Aim IV studies will use organ culture of normal and balloon-injured rat thoracic aorta, with biochemical assays of intima-media and adventitia. This proposal examines a new fundamental concept, i.e., that catecholamines are important trophic factors for SMCs and AFBs. We propose that this mechanism links the sympathetic nervous system to adaptive vascular remodeling and to pathological disease progression. The results may identify novel vascular targets for alphal-AR subtype-specific antagonists with potential therapeutic application.