AVIAN VASCULAR FUNCTION

禽类血管功能

• 批准号: 6165047
• 负责人: HIROKO NISHIMURA
• 金额: $ 23.68万
• 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 2003-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6165047
• 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.

本提案的总体目的是验证以下假设：在家禽中，血压（BP）升高和局部血流动力学力的变化会导致内皮-血管平滑肌（VSM）通信功能障碍，从而激活局部体液因子，导致VSM从收缩型向合成型调节。长期目标是阐明新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在于：1)禽类表现出年龄（性别）依赖性的高血压和高循环儿茶酚胺。2)新生内膜斑块类似于由球囊导管诱导的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段（病变易发区域），没有喂养家禽多余的脂肪或胆固醇。3)家禽VSM细胞是异质的，其中一种可能是致动脉粥样硬化的。AIM I是确定脉冲压力波的幅度（和速度）是否在病变易发区域更大，是否随着血压和血浆儿茶酚胺的升高而进一步增加。将在雏鸡、幼鸡和成熟鸡中测量沿降主动脉和血浆儿茶酚胺的脉冲压力波振幅/速度的变化。AIM II旨在确定VSM表型中的成熟/年龄依赖性调节是否与血压升高和/或循环儿茶酚胺存在因果关系。1)主动脉机械收缩，2)-肾上腺素受体阻滞剂，3)6-羟多巴胺加利血平可降低血压。AIM III旨在阐明抑制PDGF、阻断α - β整合素或用一氧化氮供体治疗是否能在体内阻止VSM表型调节和新内膜的形成。这些药物将局部或全身应用。对于AIMS II和III，将确定形态学、细胞骨架蛋白、细胞外基质、一氧化氮合酶和功能的代表性表型调节。即将到来的新信息将阐明，首先，持续升高的血压是否导致VSM表型调节/新生内膜；第二，局部血流动力学和体液因素是否触发体内表型调节；第三，VSM的表型调节是否先于新内膜斑块的形成。此外，这些研究的结果将有助于将现有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塑和动脉粥样硬化的机制。Drs。M. Kiani（血液动力学力分析）、L. C. Gerstenfeld（骨桥蛋白分子生物学）、R. F. Wideman（家禽生理学、营养学）和D. B. Thomason（肌肉分子生物学）将提供咨询。