Avian vascular function

描述（由申请人提供）：本提案的总体目的是使用一种独特的鸟类自然发生的高血压（BP）模型，测试BP的增加、选择性腹主动脉下段的血流动力学力和内皮功能障碍之间的因果关系，从而导致新内膜斑块（NPs）的形成。长期目标是阐明特定的血流动力学力和分子机制，确定性别和物种之间动脉粥样硬化易发区域的异质性。我们发现，雏鸡成熟过程中血压的逐渐升高，而不是血压的平台水平，与NP的形成和分叉上方腹主动脉下部（NP易发区）的内侧增厚有因果关系；这可以通过抗高血压治疗或口服l -精氨酸（Arg）补充剂来预防。测定降主动脉脉波速度（PWV）是衡量动脉壁硬度的一项指标，随着雄性雏鸡的成熟，该指标逐渐升高，而雌性雏鸡在性成熟后，PWV恢复到较低的水平。目的1是通过检查是否1)防止血压升高可以防止PWV升高，2)硬化的血管壁更容易受到进一步的损伤，3)性别依赖性的PWV升高可能部分取决于性腺激素，来阐明np易发区域的血流动力学和分子因素的选择性；4)病变易发区端粒长度的缩短与BP升高成反比。AIM II是为了确定1)在NP形成之前是否发生内皮功能障碍（超氧阴离子、SOA和过氧亚硝酸盐增加），而内皮一氧化氮合酶在NP易发区域相对维持良好；2)补充l -精氨酸可预防损伤主动脉的血管病变，但随后会加重病变。AIM III旨在阐明Ang II是否在禽类主动脉中发挥双重作用：在完整的血管壁中，Ang 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，Ang II是否刺激外膜中成纤维细胞的生长/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（发育期间）和NP形成（损伤主动脉）中的作用。提出的研究和结果的新方面包括：1)血流动力学力和细胞/分子机制的特征，选择np易发区域、性别和年龄；2)阐明不平衡NO和SOA水平在NP形成中的作用；3)阐明外源性Ang II受体在NP形成中的作用。拟议的项目将由五位杰出顾问提供支持。

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.