ALPHA ADRENOCEPTORS IN VASCULAR WALL GROWTH

这项提议将决定阿尔法1的局部交感神经激活是否- 肾上腺素能受体(AR)加重新生血管内膜和外膜生长 球囊血管成形术作为血管壁模型的反应 纤维增生性疾病。有证据表明，血管成形术可以增加 局部肾上腺素能神经传递。此外，α1AR的激活 诱导血管平滑肌细胞和外膜成纤维细胞的生长 (AFB)。尽管阿尔法1AR刺激被认为有助于 高血压室壁肥厚和纤维化，加剧动脉粥样硬化， 而血管成形术和支架植入后再狭窄的恶化，目前还没有研究表明 由于缺乏本地药物，直接检验了这些假说 提供系统，防止混淆全身血流动力学和 幽默动作。我们设计了一种新的系统来克服这一点 有问题。这个，加上最近开发的高度选择性的alpha1AR亚型 拮抗剂、基因敲除小鼠和反义策略将被用于 研究刺激特定字母1AR的假设 SMC和/或外膜成纤维细胞(AFB)上的亚型可能起作用 对血管内膜病变生长和外膜纤维化有重要作用。一个 黄曲霉毒素在血管壁疾病中可能的关键作用 正在浮现。我们已经开发了一个独特的模型系统来研究这些 体内和体外的细胞，并做出了耐人寻味的发现 黄曲霉毒素B细胞在细胞骨架的排列上不同于其他成纤维细胞 它们表达的蛋白质，以及它们意想不到的表达 多个AlphaAR子类型。此外，AFB经历了一个显著的 可能在血管壁中起重要作用的表型转化 疾病。目标1将确定Alpha1AR刺激是否直接诱导 正常血管壁的生长，重要的是，如果它恶化 损伤后新生血管内膜生长和外膜纤维化。目标2将 确定损伤如何改变血管内膜、中层和中层的α-AR表达 外膜；以及SMC和AFB上哪个α1-AR亚型(S)增强 正常和受损的室壁生长。AIM 3将检查Alpha1AR 刺激通过增加SMC恶化新生内膜或外膜的生长 和/或黄曲霉毒素在体内的增殖、迁移或基质形成。目标 4将使用培养的SMC和AFB来测试我们的假设 刺激增加或协同特定的多肽生长 促进SMC和AFB表型转化的因子(S)， 扩散、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.