EFFECTS OF MODULATION OF PRESSURE AND FLOW ON VESSEL WALL ADAPTATION

压力和流量调节对血管壁适应的影响

• 批准号: 5213148
• 负责人: SEYMOUR GLAGOV
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5213148
• 关键词: Macaca fascicularis; aorta coarctation; artery; atherosclerotic plaque; blood pressure; cell cycle; collagen; collagenase; elastases; elastin; endopeptidases; gene expression; heart rate; hemodynamics; human tissue; hypercholesterolemia; hyperplasia; in situ hybridization; laboratory rabbit; postmortem; proteolysis; restenosis; tensile strength; vasodilation

The objective of the proposed research is to identify and relate the mechanisms, in vivo in suitable experimental models, which a) regulate the adaptation of arteries to changes in flow and pressure, b) determine the localization of plaques under conditions of hypercholesterolemia, and c) account for the interactions among hypercholesterolemia, plaque formation and the adaptive mechanisms to altered wall shear and tensile stresses. We have previously described a close relationship between wall shear stress and plaque localization, and developed an experimental model of lesion prone and lesion resistant regions. We have characterized the quantitative relationships among wall shear stress, tensile stress and artery wall infrastructure. These findings have revealed that artery wall adaptation to altered flow and pressure, plaque localization and the compensatory enlargement and modelling of arteries and plaques are a closely related phenomena. The proposed investigations will be carried out at the structural, cellular and molecular level, utilizing rabbit models designed to increase flow (arterio-venous fistula), decrease flow (carotid outflow ligation), alter pressure and establish lesion prone and lesion resistant regions (aortic coarctation). Our methods include ultrastructural, morphometric and chemical determinations of artery wall composition (elastin, collagen (Types I, III, IV and their respective proteases), and quantitation of cell proliferation and hypertrophy. Characterization of gene expression for these features, including in situ hybridization is expected to clarify both the sequence and spatial localization of the elicited changes in the absence and presence of hypercholesterolemia and plaque formation. An essential feature will be the correlation of spatial localization of our findings with the corresponding quantitative flow field characterizations in Project 0031 and the related biomechanical-cellular interactions revealed in Project 0034. Our research should provide new insights into the nature and limits of vessel wall adaptation to altered mechanical conditions and to the formation of plaques.

拟议研究的目标是确定和联系 在适当的实验模型中的体内机制，其中a)调节 动脉对流量和压力变化的适应性，b)决定 高胆固醇血症条件下斑块的定位，以及c) 解释高胆固醇血症、斑块形成之间的相互作用 以及对改变的壁剪应力和拉应力的适应机制。我们 之前已经描述了壁面剪应力之间的密切关系 和斑块定位，并开发了病变的实验模型 易感区域和病变抵抗区。我们已经描述了数量上的 管壁剪应力、拉应力与动脉壁的关系 基础设施。这些发现揭示了动脉壁适应 改变血流和压力，斑块定位和代偿性 动脉和斑块的扩大和模型化是密切相关的 现象。拟议的调查将在 结构、细胞和分子水平，利用设计的兔子模型 增加血流量(动静脉瘘)，减少血流量(颈动脉流出 结扎)，改变压力，建立病变倾向和病变抵抗 区域(主动脉缩窄)。我们的方法包括超微结构， 动脉壁成分的形态计量学和化学测定 (弹性蛋白、胶原蛋白(I型、III型、IV型及其各自的蛋白酶)和 细胞增殖和肥大的定量。特征描述 这些特征的基因表达，包括原位杂交 预计将澄清 引起高胆固醇血症的存在和不存在的变化 斑块形成。一个基本特征将是空间的相关性 我们的发现与相应的定量流场的本地化 项目0031中的特征及其相关的生物力学细胞 0034项目中揭示的相互作用。我们的研究应该提供新的 对血管壁适应改变的本质和限度的洞察 机械条件和斑块的形成。