This proposal will determine if local sympathetic activation of alpha1- adrenergic receptors (AR) worsens the neointimal and adventitial growth responses to balloon angioplasty, as a model of vascular wall fibroproliferative disease. Evidence suggests that angioplasty augments local adrenergic neurotransmission. Furthermore, alpha1AR activation induces growth of smooth muscle cells (SMC) and adventitial fibroblasts (AFB). Although alpha1AR stimulation has been proposed to contribute to hypertensive wall hypertrophy and fibrosis, exacerbate atherosclerosis, and to worsen restenosis after angioplasty and stenting, no studies have directly examined these hypotheses because of absence of local drug delivery systems that prevent confounding systemic hemodynamic and humoral actions. We have devised a novel system that overcomes this problem. This, plus recently developed highly selective alpha1AR subtype antagonists, knockout mice and antisense strategies, will be used to investigate the hypothesis that stimulation of a specific alpha1AR subtype on SMCs and/or adventitial fibroblasts (AFB) may contribute importantly to intimal lesion growth and adventitial fibrosis. A possible key role for AFBs in vascular wall disease is just now emerging. We have developed a unique model system for study of these cells in vivo and in vitro, and have made the intriguing finding that AFBs cells differ from other fibroblasts in the array of cytoskeletal proteins that they express, and in their unexpected expression of multiple alphaAR subtypes. Moreover, AFBs undergo a remarkable phenotypic transformation that may be important in vascular wall disease.
Aim 1 will determine if alpha1AR stimulation directly induces growth of the normal vascular wall, and importantly, if it worsens neointimal growth and adventitial fibrosis after injury.
Aim 2 will determine how injury alters alphaAR expression in the intima, media and adventitia; and which alpha1-AR subtype(s) on SMCs and AFBs augments normal and injured wall growth.
Aim 3 will examine if alpha1AR stimulation worsens neointimal or adventitial growth by augmenting SMC and/or AFB proliferation, migration, or matrix elaboration in vivo.
Aim 4 will use cultured SMCs and AFBs to test our hypothesis that alpha1AR stimulation adds to-or synergizes with- a specific peptide growth factor(s) to promote SMC and AFB phenotypic transformation, proliferation, migration and/or matrix accumulation.
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