Avian vascular function

禽类血管功能

• 批准号: 7037610
• 负责人: HIROKO NISHIMURA
• 金额: $ 24.95万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037610
• 关键词: age difference; aging; angiotensin II; angiotensin receptor; antihypertensive agents; aorta; arginine; atherosclerosis; blood pressure; chickens; disease /disorder model; disease /disorder prevention /control; gender difference; hemodynamics; hypertension; nitric oxide; nitric oxide synthase; pathologic process; peroxynitrites; pulse pressure wave; sex hormones; superoxides; telomere; vascular endothelium; vascular smooth muscle; vasomotion

DESCRIPTION (provided by applicant): The overall aim of this proposal is to test, using a unique avian naturally occurring high blood pressure (BP) model, a causal relationship among incremental increases in BP, hemodynamic forces selective to the lower segment of the abdominal aorta and endothelial dysfunction, leading to the formation of neointimal plaques (NPs). A long-term goal is to elucidate the specific hemodynamic forces and molecular mechanisms that determine the heterogeneity of atherosclerosis-prone regions between genders and among species. We found that incremental increases in BP during maturation of chicks, but not plateau levels of BP, are causally related to NP formation and medial thickening in the lower part of the abdominal aorta above the bifurcation (NP-prone area); this can be prevented by antihypertensive treatment or by oral L-arginine (Arg) supplement. Pulse wave velocity (PWV) measured in the descending aorta, an index for arterial wall stiffness, becomes progressively higher with maturation in male chicks, whereas in females, PWV was restored to lower levels after sexual maturation. AIM I is to elucidate hemodynamic and molecular factors selective for NP-prone regions by examining whether 1) preventing the rise in BP prevents the elevation of PWV, 2) hardened vascular walls are more susceptible to further injury, 3) gender-dependent increases in PWV may partly depend on gonadial hormones; and 4) shortening of telomere length in the lesion-prone area occurs inversely to the rise in BP. AIM II is to determine whether 1) endothelial dysfunction occurs (increased superoxide anion, SOA, and peroxynitrite) prior to NP formation, whereas endothelial nitric oxide synthase is relatively well maintained, in the NP-prone area; and 2) L-Arg supplement initially prevents, but later aggravates, vascular lesions in injured aorta. AIM III is to elucidate whether Ang II exerts a dual action in fowl aorta: whether, in intact vascular walls, Ang II helps maintain vascular wall integrity via an endothelial mechanism, whereas in injured walls, it stimulates fibroblast growth/mobilization in adventitia. We will examine the involvement of endothelium-dependent hyperpolarization factor (EDHF)/K* channels in Ang II-induced endothelial mechanism and 2) the role of Ang II, via adventitial receptors, in vascular growth (during development) and NP formation (injured aorta). Novel aspects of the proposed studies and outcome include: 1) characterization of hemodynamic forces and cellular/molecular mechanisms selective to the NP-prone area, gender, and age; 2) elucidation of the roles of unbalanced NO and SOA levels in NP formation; and 3) elucidation of the role of the adventitial Ang II receptors in NP formation. The proposed projects will be supported by five distinguished consultants.

描述(由申请人提供)：这项建议的总体目标是，使用独特的禽类自然发生高血压(BP)模型，测试血压增加、选择腹主动脉下段的血流动力学力量和导致新内膜斑块(NPs)形成的内皮功能障碍之间的因果关系。一个长期的目标是阐明决定动脉粥样硬化易感区域在性别和物种之间的异质性的特定血流动力学力量和分子机制。我们发现，雏鸡成熟期血压的递增升高，而不是平台水平的血压，与腹主动脉分叉以上下部(NP易发区)的NP形成和中层增厚有关；这可以通过降压治疗或口服L精氨酸(Arg)来预防。在公鸡降主动脉测得的脉搏波速度(PWV)是动脉壁硬度的一个指标，随着雏鸡的成熟，脉搏波速度(PWV)逐渐升高，而在雌性雏鸡，脉搏波速度在性成熟后恢复到较低的水平。目的1)通过检测是否1)阻止血压升高阻止PWV升高，2)硬化的血管壁更容易受到进一步的损伤，3)PWV的性别依赖性增加可能部分依赖于性激素，以及4)病变易发区域端粒长度缩短与BP升高成反比，阐明血液动力学和分子因素对NP易发区的选择性。目的II确定在NP易发部位，是否在NP形成前发生内皮功能障碍(超氧阴离子、超氧化物歧化酶和过氧亚硝酸盐增加)，而内皮一氧化氮合酶相对维持良好；2)补充L-精氨酸最初可以预防，但后来会加重受损的主动脉血管病变。目的III阐明血管紧张素转换酶II是否在鸡主动脉发挥双重作用：在完好的血管壁上，血管紧张素转换酶II是否通过内皮机制帮助维持血管壁的完整性，而在受损的血管壁上，它是否刺激外膜成纤维细胞的生长/动员。我们将探讨内皮依赖性超极化因子(EDHF)/K*通道在Ang II诱导的内皮机制中的作用，以及2)Ang II通过外膜受体在血管生长(发育过程中)和NP形成(损伤的主动脉)中的作用。新的研究和结果包括：1)表征血液动力学和细胞/分子机制，选择性地选择NP的易感区域、性别和年龄；2)阐明NO和SOA水平失衡在NP形成中的作用；以及3)阐明外膜Ang II受体在NP形成中的作用。拟议的项目将由五位杰出的顾问提供支助。