Avian vascular function

描述（由申请方提供）：本提案的总体目的是使用独特的禽类自然发生的高血压（BP）模型，检测BP递增、选择性腹主动脉下段血流动力学力和内皮功能障碍（导致新生内膜斑块（NP）形成）之间的因果关系。一个长期的目标是阐明特定的血流动力学力量和分子机制，决定了性别和物种之间的动脉粥样硬化易感区域的异质性。我们发现，在鸡的成熟过程中，BP的增量增加，但不是平台水平的BP，是有因果关系的NP形成和中膜增厚的腹主动脉的下部以上的分叉（NP-倾向的地区），这可以防止抗高血压治疗或口服L-精氨酸（Arg）的补充。脉搏波速度（PWV）测量降主动脉，动脉壁硬度的指数，变得越来越高，与成熟的雄性小鸡，而在女性，PWV恢复到较低的水平后，性成熟。目的：通过检查1）阻止血压升高是否会阻止PWV升高，2）硬化的血管壁是否更容易受到进一步损伤，3）PWV的性别依赖性增加可能部分取决于性腺激素，以及4）病变倾向区域端粒长度的缩短是否与血压升高相反，来阐明选择性用于NP倾向区域的血流动力学和分子因素。目的II是确定1）内皮功能障碍是否在NP形成之前发生（增加的超氧阴离子、SOA和过氧亚硝酸盐），而内皮型一氧化氮合酶在NP倾向区域中相对良好地维持;和2）L-Arg补充最初预防，但随后减轻，损伤的主动脉中的血管病变。目的III是阐明血管紧张素II是否在家禽主动脉中发挥双重作用：在完整的血管壁中，血管紧张素II是否通过内皮机制帮助维持血管壁的完整性，而在损伤的血管壁中，它刺激外膜成纤维细胞的生长/动员。我们将研究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参与，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（受损主动脉）中的作用。所提出的研究和结果的新方面包括：1）对NP倾向区域、性别和年龄具有选择性的血流动力学力和细胞/分子机制的表征; 2）阐明不平衡的NO和SOA水平在NP形成中的作用;和3）阐明外膜Ang II受体在NP形成中的作用。建议的项目将得到五位杰出顾问的支持。

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.