Alpha-Adrenoceptors in Vascular Wall Growth

描述（由申请人提供）：在过去的十年中，该基金支持的工作发现去甲肾上腺素（NE）在体外和体内诱导平滑肌细胞（SMC）和外膜成纤维细胞的生长。这种生长因子样活性得到了其他人的证实，在病理性（例如，球囊损伤）和适应性生理设置（例如，血流重构），甚至在交感神经紧张的基线水平。负责的11-肾上腺素受体（AR）类型不同于通常介导收缩的类型。在上一个资助期的主要发现是：（1）肾上腺素能诱导的生长被推广到除损伤外的其他环境，例如，肺动脉高压中的内膜增生、侧支壁增厚和低血流诱导的负性（向内）肥大性重塑（FINR）。(2)确定了关键信号元件：11-AR AE NAD（P）H-氧化酶AE ROS/H2 O2 AE pro-HB-EGF-裂解AE HB-EGF AE EGFR AE Raf 1 AE MEK AE ERK 1/2 AE细胞肥大、增殖和迁移、胶原积聚、内膜、中膜和外膜增厚。这些发现不仅与疾病有潜在的相关性，而且它们还将功能附加到SMC和外膜成纤维细胞上存在的特定11- AR亚型，这些亚型迄今为止尚未被赋予功能。最近出现了对人体中该机制的可能支持;使用11 A-AR拮抗剂长期治疗前列腺肥大伴随动脉粥样硬化诱导的缺血性心脏病症状的发生减少72%（在第4节中进行了综述）。因此，现在重要的是确定这种营养途径是否存在于人类血管中，以及它是否有助于或阻止动脉粥样硬化形成（目标I和II）。虽然HB-EGF是上皮生长、伤口愈合和癌症的主要调节剂，但对其在血管壁细胞中的作用知之甚少。补充上述发现，我们的初步工作的目的III已获得有趣的证据表明，HB-EGF可能作为一个一般的信号联系在血管壁生长。例如，我们发现HB-EGF是肾上腺素能生长和FINR所必需的，FINR是一种具有动脉粥样硬化形成共同特征的模型。虽然EC、SMC和巨噬细胞在体外释放HB-EGF，但它们是否在体内释放尚不清楚（目的III）。这些研究是必要的目的IV，这将测试新的假设，ROSAEHB-EGF信号在动脉粥样硬化是重要的。这些研究延续了该项目的长期目标，以更好地了解适应性条件和血管疾病中血管壁生长和重塑的调节。公共卫生相关性：虽然儿茶酚胺（肾上腺素和去甲肾上腺素）的急性增加有益于收缩血管并加强运动和压力情况下的心脏活动，但血管疾病的风险因素（例如，慢性压力、衰老、高盐饮食、糖尿病、肥胖、吸烟、男性、高血压和久坐不动的生活方式）。该项目旨在扩展我们以前在啮齿动物中的研究，这些研究表明，儿茶酚胺的慢性增加具有生长因子样（营养）作用，可能导致或恶化血管疾病（例如，动脉粥样硬化，动脉硬化，再狭窄和旁路移植失败），进入研究，可能导致新的治疗方法，以阻止这一途径在人类血管疾病。因此，我们将研究人类血管：1）检查儿茶酚胺是否是营养性的，特别是那些有血管疾病早期迹象的，2）确定负责的细胞信号传导机制，以及3）还在大鼠和小鼠中进行研究以更好地理解信号传导机制（特别是HB-EGF），测试儿茶酚胺和HB-EGF是否使实验性动脉粥样硬化恶化，看看我们是否能通过阻断这些信号成分来减轻动物模型中的疾病。

DESCRIPTION (provided by applicant): In the past decade, work supported by this grant has found that norepinephrine (NE) induces growth of smooth muscle cells (SMCs) and adventitial fibroblasts in vitro and in vivo. This growth factor-like activity, con- firmed by others, is accentuated in arteries undergoing hypertrophic changes in pathologic (e.g., balloon injury) and adaptive physiologic settings (e.g., flow remodeling), even at baseline levels of sympathetic tone. The responsible 11-adrenoceptor (AR) type differs from the one that generally mediates constriction. Major findings during the previous grant period were: (1) Adrenergic-induced growth is generalized to other settings besides injury, e.g., intimal hyperplasia in pulmonary hypertension, collateral wall thickening, and low-Flow Induced Negative (inward) hypertrophic Remodeling (FINR). (2) The key signaling elements were identified: 11-AR AE NAD(P)H-oxidase AE ROS/H2O2 AE pro-HB-EGF-cleavage AE HB-EGF AE EGFR AE Raf1 AE MEK AE ERK1/2 AE cell hypertrophy, proliferation and migration, collagen accumulation, thickening of intima, media and adventitia. Not only do these findings have potential relevance to disease, but they also attach a function to particular 11- AR subtypes present on SMCs and adventitial fibroblasts that until now had not been ascribed a function. Possible support for this mechanism in humans has recently appeared; chronic treatment of prostatic hypertrophy with an 11A-AR antagonist was accompanied by a 72% reduction in the development of symptoms of atherosclerosis-induced ischemic heart disease (reviewed in Section 4). Thus, it is now important to determine if this trophic pathway exists in human vessels and if it contributes to or worsens atherogenesis (Aims I & II). Although HB-EGF is a major regulator of epithelial growth, wound healing and cancer, little is known about its role in vascular wall cells. Complimenting the above findings, our preliminary work for Aim III has obtained intriguing evidence that HB-EGF may serve as a general signaling nexus in vascular wall growth. For example, we find HB-EGF is required for both adrenergic growth and FINR-- a model with some features common to atherogenesis. While ECs, SMCs and macrophages release HB-EGF in vitro, whether they do in vivo is un- known (Aim III). These studies are requisite to Aim IV which will test the novel hypothesis that ROSAEHB-EGF signaling is important in atherosclerosis. These studies continue the long-term goal of this project to better understand the regulation of vascular wall growth and remodeling in adaptive conditions and vascular disease. PUBLIC HEALTH RELEVANCE: While acute increases in catecholamines (adrenalin and noradrenaline) act beneficially to constrict blood vessels and strengthen the heart's activity in exercise and stressful situations, continuously high levels are induced by risk factors for vascular disease (e.g., chronic stress, aging, high salt diet, diabetes, obesity, smoking, male sex, hypertension, and sedentary lifestyle). This project seeks to extend our previous investigations in rodents, which have shown that chronic increases in catecholamines have growth factor-like (trophic) actions that may contribute to or worsen vascular disease (e.g., atherosclerosis, arteriosclerosis, restenosis and bypass graft failure), into studies that may lead to new treatments to block this pathway in human vascular disease. Thus, we will study human vessels to: 1) examine if catecholamines are trophic, especially those with early signs of vascular disease, 2) identify the responsible cellular signaling mechanisms, and 3) also conduct studies in rats and mice to better understand the signaling mechanisms (in particular HB- EGF), test whether catecholamines and HB-EGF worsen experimental atherosclerosis, and see if we can lessen disease in animal models by blocking these signaling components.