Alpha-Adrenoceptors in Vascular Wall Growth

描述(申请人提供)：在过去的十年里，由该基金支持的工作发现去甲肾上腺素(NE)在体外和体内都能诱导血管平滑肌细胞(SMCs)和外膜成纤维细胞的生长。这种生长因子样活性被其他人证实，在经历肥厚性病理变化(例如球囊损伤)和适应性生理变化(例如血流重塑)的动脉中，即使在交感神经张力的基线水平上也是如此。负责的11-肾上腺素能受体(AR)类型不同于一般介导收缩的类型。前一次赠款期间的主要发现是：(1)肾上腺素能诱导的生长除损伤外，还可推广到其他环境，例如，肺动脉高压中的内膜增生、侧支管壁增厚和低流量诱导的负性(向内)肥厚重塑(FINR)。(2)确定了11-AR、AENAD(P)H-氧化酶、AEROS/H-O2、AEPro-HB-EGF-裂解AEHB-EGF、AEEGFR、AERAF1、AEMEK、AEERK1/2AE细胞肥大、增殖和迁移、胶原堆积、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，而且还与SMC和外膜成纤维细胞上存在的特定11-AR亚型有关，这些亚型到目前为止还没有被归因于功能。最近出现了对人类这一机制的可能支持；用11A-AR拮抗剂慢性治疗前列腺肥大伴随着动脉粥样硬化诱导的缺血性心脏病症状的发展减少了72%(在第4节回顾)。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，以及它是促进还是恶化动脉粥样硬化(目标I和II)。尽管HB-EGF是上皮生长、伤口愈合和癌症的主要调节因子，但人们对其在血管壁细胞中的作用知之甚少。作为对上述发现的补充，我们对AIM III的初步工作已经获得了有趣的证据，即HB-EGF可能在血管壁生长中作为一般的信号联系。例如，我们发现HB-EGF对肾上腺素能生长和FINR都是必需的--这是一种具有动脉粥样硬化形成共同特征的模型。虽然ECs、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(Aim III)。这些研究是Aim IV所必需的，它将检验ROSAEHB-EGF信号在动脉粥样硬化中重要的这一新假说。这些研究延续了该项目的长期目标，以更好地了解适应条件和血管疾病中血管壁生长和重塑的调节。与公共健康相关：虽然儿茶酚胺(肾上腺素和去甲肾上腺素)的急剧增加有益于在运动和压力情况下收缩血管和增强心脏活动，但持续的高水平是由血管疾病的风险因素(例如，慢性应激、衰老、高盐饮食、糖尿病、肥胖、吸烟、男性、高血压和久坐的生活方式)引起的。该项目旨在将我们之前对啮齿动物的研究扩展到可能导致或加重血管疾病(例如，动脉粥样硬化、动脉硬化、再狭窄和搭桥失败)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，可能导致在人类血管疾病中阻断这一途径。因此，我们将对人类血管进行研究，以：1)检验儿茶酚胺是否具有营养作用，尤其是那些有血管疾病早期迹象的血管；2)确定负责的细胞信号机制；3)还在大鼠和小鼠身上进行研究，以更好地了解信号机制(特别是HB-EGF)，测试儿茶酚胺和HB-EGF是否会加剧实验性动脉粥样硬化，并看看是否可以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.