AVIAN VASCULAR FUNCTION

禽类血管功能

• 批准号: 6637479
• 负责人: HIROKO NISHIMURA
• 金额: $ 15.05万
• 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 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637479
• 关键词: age difference; antihypertensive agents; aorta; blood chemistry; catecholamines; cell cell interaction; cell communication molecule; chickens; hemodynamics; hypertension; integrins; nitric oxide; platelet derived growth factor; pulse pressure wave; vascular endothelium; vascular smooth muscle; vasomotion

The overall aim of this proposal is to test the hypothesis that, in fowl, elevation of blood pressure (BP) and changes in local hemodynamic forces causally induce dysfunction of endothelium-vascular smooth muscle (VSM) communication that activates local humoral factors resulting in VSM modulation from contractile to synthetic phenotypes. A long-term goal is to elucidate the cellular mechanism of neointimal lesions and its relation to atherosclerosis. The unique aspects of the avian vascular model include: 1) fowl show age- (sex-) dependent high BP and high circulating catecholamines. 2) Neointimal plaques that resemble those formed by a balloon catheter-induced endothelium injury develop spontaneously at early ages, most frequently in the distal segment of the abdominal aorta (lesion- prone area), without feeding the fowl excess fat or cholesterol. 3) Fowl VSM cells are heterogenous, and one type may be atherogenic. AIM I is to determine whether the magnitude (and velocity) of the pulse pressure wave are greater in the lesion-prone area and whether they further increase as BP and plasma catecholamines become higher. Changes in pulse pressure wave amplitude/velocity along the decending aorta and plasma catecholamines will be measured in chicks, pullets, and mature chickens. AIM II is to determine whether maturation/age-dependent modulation in VSM phenotypes shows a causal relationship with elevated BP and/or circulating catecholamines. BP will be lowered by 1) mechanical constriction of the aorta, 2) beta-adrenoceptor blocker, and 3) 6-hydroxydopamine plus reserpine. AIM III is to elucidate whether inhibition of PDGF, blockade of alpha beta integrins, or treatment with nitric oxide donor prevents VSM phenotypic modulation and neointima formation in vivo. The drugs will be locally or systemically applied. For AIMS II and III, representative phenotypic modulations in morphology, cytoskeletal protein, extracellular matrix, nitric oxide synthase, and function will be determined. The novel information forthcoming will elucidate, first, whether sustained elevation of BP causally induces VSM phenotypic modulation/neointima; second, whether local hemodynamic and humoral factors trigger phenotypic modulation in vivo; and, third, whether phenotypic modulation of VSM precedes the development of neointimal plaques. Furthermore, the outcome derived from the proposed studies will help integrate available cellular and molecular information into intact animal levels and help us understand the mechanism of vascular remodeling and atherosclerosis in humans and other mammals. Drs. M. Kiani (analysis of hemodynamic forces), L. C. Gerstenfeld (osteopontin molecular biology), R. F. Wideman (poultry physiology, nutrition), and D. B. Thomason (muscle molecular biology) will provide consultation.

这一建议的总体目的是检验一种假设，即在家禽中，血压(BP)的升高和局部血流动力的变化导致内皮-血管平滑肌(VSM)通讯功能障碍，从而激活局部体液因子，导致VSM从收缩表型向合成表型的调节。一个长期的目标是阐明新生内膜病变的细胞机制及其与动脉粥样硬化的关系。禽类血管模型的独特之处包括：1)禽类表现出年龄(性别)依赖性的高血压和高儿茶酚胺循环。2)新血管内膜斑块类似于球囊导管致内皮损伤形成的斑块，在早期自发形成，最常见的是在腹主动脉远端(病变易发部位)，而不喂饲家禽过多的脂肪或胆固醇。3)鸡VSM细胞具有异质性，其中一种可能是致动脉粥样硬化的细胞。目的确定病变易发部位脉压波的波幅(和波速)是否较大，是否随着血压和血浆儿茶酚胺的升高而进一步增大。将在雏鸡、小鸡和成熟鸡身上测量沿降主动脉的脉压波幅度/速度和血浆儿茶酚胺的变化。目的II确定VSM表型的成熟/年龄依赖性调节是否与血压和/或循环中的儿茶酚胺升高存在因果关系。通过1)机械收缩主动脉，2)β受体阻滞剂，以及3)6-羟基多巴胺加利血平来降低血压。目的III阐明抑制PDGF、阻断α-β整合素或一氧化氮供体治疗是否能阻止体内VSM的表型改变和新生内膜的形成。这些药物将在局部或全身应用。对于AIMS II和III，将确定在形态、细胞骨架蛋白、细胞外基质、一氧化氮合酶和功能方面具有代表性的表型调节。即将公布的新信息将阐明，第一，血压持续升高是否导致VSM表型调节/新内膜形成；第二，局部血流动力学和体液因素是否在体内触发表型调节；第三，VSM表型调节是否先于新生内膜斑块的发展。此外，拟议研究的结果将有助于将可用的细胞和分子信息整合到完整的动物水平，并帮助我们了解人类和其他哺乳动物血管重构和动脉粥样硬化的机制。M.Kiani博士(血流动力分析)、L.C.Gerstenfeld博士(骨桥蛋白分子生物学)、R.F.Wideman博士(家禽生理学、营养学)和D.B.Thomason博士(肌肉分子生物学)将提供咨询。