AVIAN VASCULAR FUNCTION--INTERACTION WITH ANGIOTENSIN

描述：这项提案的总体目标是调查 VES单元在控制血管功能方面的优势，利用一种独特的 血管紧张素与禽类血管细胞的相互作用。长期目标 将阐明血管紧张素转换酶的细胞和分子机制 交流和确定局部体液和血液动力学因素 调节正常和受损血管中的VES单位。这个 鸟类血管模型的独特之处包括：1)鸟类有 血压和血浆儿茶酚胺升高，两者都显示 自发性血管内皮损伤致血管 新生血管内膜斑块。2)两种类型的血管平滑肌细胞 似乎是存在的，其中一种可能是致动脉粥样硬化。3)和施展 内皮依赖性血管松弛 因子(EDRF)/cGMP和通过释放儿茶酚胺的升压作用； 这些作用是选择性地可抑制的。4)前列环素合成酶 在禽类的主动脉中似乎不存在。申请人假设 高灌注性损伤所致的内皮功能障碍 压力和沟通障碍可能会导致或加重， 易发生动脉粥样硬化的血管内膜增生性病变。这个 Ang与家禽血管细胞的双重相互作用将提供一种 研究VES单位在监管中的作用的有用工具 血管功能正常和受损。第一个目标是描述年龄- 家禽VES单位(或与血压相关)的表型变化 主动脉专注于：1)内皮功能(内皮依赖 松弛和通透性)和细胞信号(cGMP/一氧化氮) 2)血管紧张素转换酶功能(收缩和促进生长)和钙 信号转导及其与血压和新生血管内膜的关系 增殖性斑块。将使用四个年龄组，代表 建立血管病变和血液的前后情况 压力。此外，形态和生理特性将 自然发育与血管内皮损伤的比较 新生内膜斑块细胞。目标二是确定刺激是否 与或抑制α-肾上腺素能对血管内皮细胞功能的影响 受体有助于维持正常的VES单位功能，并防止 血管斑块的发展以及血管内皮细胞是否相反 损伤(通过EDRF/一氧化氮合酶抑制或内皮 损伤)或增加的儿茶酚胺加速VES单位功能障碍和 新生内膜增生，可能导致血压升高。 血管紧张素转换酶和抑制剂通过渗透性微泵注入， 将如上所述检查VES单元的形态和功能。安格 与禽类血管系统的相互作用将提供一种独特的 研究VES单位在脑内的作用和细胞机制的模型 血管功能正常和受损的控制。

DESCRIPTION: The overall aim of this proposal is to investigate the role of the VES unit in the control of vascular function, utilizing a unique interaction between ANG and the avian vascular cells. A long-term goal will be to elucidate the cellular and molecular mechanisms of the VES communication and to determine local humoral and hemodynamic factors that regulate the VES unit in normal and impaired blood vessels. The unique aspects of the avian vascular model include: 1) Birds have elevated blood pressure and plasma cateholamines and show both spontaneously developed and endothelium injury- induced vascular neointimal plaques. 2) Two types of vascular smooth muscle (VSM) cells appear to be present, one of which may be atherogenic. 3) ANG exerts endothelium-dependent vasorelaxation via endothelium-derived relaxing factor (EDRF)/cGMP and vasopressor action by releasing catecholamines; these actions are selectively inhibitable. 4) Prostacyclin synthase appears absent in fowl aortae. The applicant hypothesizes that endothelial dysfunction, due to damage caused by high perfusion pressure, and impaired VES communication may lead to, or aggravate, neointimal proliferative lesions in atherogenesis- prone vessels. The dual interaction of ANG with vascular cells in fowl will provide a useful tool for studying the role of the VES unit in the regulation of normal and impaired vascular function. Aim one is to characterize age- (or blood pressure-) related phenotype changes of the VES unit of fowl aortae focusing on: 1) endothelial function (endothelium-dependent relaxation and permeability) and cellular signals (cGMP/nitric oxide) and 2) VSM function (contraction and growth promotion) and calcium signalling and their relationship to blood pressure and neointimal proliferative plaques. Four age-groups will be used, representing those preceding and following establishment of vascular lesions and blood pressure. Furthermore, morphological and physiological properties will be compared between naturally developed and endothelium injury-induced neointimal plaque cells. Aim two is to determine whether stimulation of endothelial function by ANG or inhibition of alpha-adrenergic receptors helps maintain normal VES unit function and prevents development of vascular plaques and whether, in contrast, endothelial impairment (by EDRF/nitric oxide synthase inhibition or endothelium injury) or increased catecholamines accelerate VES unit dysfunction and neointimal hyperplasia, possibly leading to elevation of blood pressure. ANG and inhibitors will be infused by osmotic minipump, and the morphology and function of the VES unit will be examined as above. ANG interaction with the vascular system in fowl will provide an unique model for studying the role and cellular mechanism of the VES unit in the control of normal and impaired vascular function.