ALPHA ADRENOCEPTORS IN VASCULAR WALL GROWTH

这项提议将确定是否局部交感神经激活α 1- 肾上腺素能受体（AR）抑制血管内膜和外膜的生长 对球囊血管成形术的反应，作为血管壁模型 纤维增生性疾病有证据表明血管成形术 局部肾上腺素能神经传递。此外，α 1 AR激活 诱导平滑肌细胞（SMC）和外膜成纤维细胞生长 （AFB）。尽管已经提出α 1 AR刺激有助于 高血压壁肥大和纤维化，加剧动脉粥样硬化， 并加重血管成形术和支架植入术后的再狭窄， 由于缺乏当地药物， 输送系统可防止混淆全身血液动力学， 体液作用我们设计了一个新的系统来克服这个问题 问题.再加上最近开发的高选择性α 1 AR亚型 拮抗剂，敲除小鼠和反义策略，将用于 研究刺激特定的α 1 AR SMC和/或外膜成纤维细胞（AFB）上的亚型可能有助于 这对于内膜损伤生长和外膜纤维化是重要的。一 AFB在血管壁疾病中可能的关键作用 正在浮现我们开发了一个独特的模型系统，用于研究这些 细胞在体内和体外，并取得了有趣的发现， AFB细胞与其他成纤维细胞的细胞骨架阵列不同， 它们表达的蛋白质，在它们意想不到的表达中， 多种α AR亚型此外，AFB经历了一个显着的 表型转化可能是重要的血管壁 疾病目的1将确定α 1 AR刺激是否直接诱导 正常血管壁的生长，重要的是， 损伤后新生内膜生长和外膜纤维化。目标2将 确定损伤如何改变内膜、中膜和 外膜; SMC和AFB上的α 1-AR亚型增强 正常和受损的壁生长。目标3将检查alpha 1AR是否 通过增加SMC刺激新生内膜或外膜生长 和/或体内AFB增殖、迁移或基质加工。目的 4将使用培养的SMC和AFB来验证我们的假设， 刺激增加-或协同-一个特定的肽生长 促进SMC和AFB表型转化的因子， 增殖、迁移和/或基质积累。

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.