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）：该提案的总体目的是使用自然存在的高血压（BP）模型进行测试，BP的增量增加之间的因果关系，对腹主动脉下部的下部选择性的血液动力学选择，并导致内皮功能障碍的下部，导致Neinerimalimal plaaques（Nps）（NPS）（NPS）。一个长期的目标是阐明决定性动脉粥样硬化区域和物种之间容易发生动脉粥样硬化区域的异质性的特定血流动力和分子机制。我们发现，在雏鸡成熟期间，BP的增量增加，而不是平稳的BP水平，与NP形成和内侧增厚均与分叉上方（NP-易于负责的区域）的腹主动脉下部的内侧增厚有关。这可以通过降压治疗或口服L-精氨酸（ARG）补充剂来预防。在雄性雏鸡的成熟时，在降主动脉中测得的脉搏波速度（PWV）逐渐更高，而在女性中，PWV在性成熟后恢复至较低的水平。目的I是通过检查1）防止BP的增加是否防止PWV的升高来阐明对NP易发区域选择性的血液动力学和分子因素，2）硬化的血管壁更容易受到进一步的损伤，3）PWV中PWV的性别依赖性增加可能部分依赖于肿瘤的激素； 4）偏用病变区域中端粒长度的缩短成反比BP的增长。 AIM II是确定1）在NP形成之前是否发生内皮功​​能障碍（增加的超氧化物阴离子，SOA和过氧硝酸盐），而在NP-PRONE区域，内皮一氧化氧化物合酶的维持相对良好； 2）L-ARG补充剂最初可防止，但后来加剧了受伤主动脉的血管病变。 AIM III是要阐明ANG II是否在Fowl主动脉中发挥双重作用：在完整的血管壁中，Ang II是否有助于通过一种内皮机制来维持血管壁完整性，而在受伤的壁中，它刺激了外膜中的成纤维细胞生长/动员。我们将研究ANG II引起的内皮机制中内皮依赖性超极化因子（EDHF）/K*通道的参与，以及2）ANG II通过外在受体，血管生长（在发育过程中）和NP形成（损伤AORTA）的作用。拟议的研究和结果的新方面包括：1）对NP易发性区域，性别和年龄选择性的血液动力学和细胞/分子机制的表征； 2）阐明NP形成中不平衡的NO和SOA水平的作用； 3）阐明了外在ANG II受体在NP形成中的作用。拟议的项目将得到五名杰出顾问的支持。