STUDIES ON ENDOTHELIUM IN RELATION TO ATHEROGENESIS

内皮与动脉粥样硬化相关的研究

• 批准号: 3350595
• 负责人: Peter Francis Davies
• 金额: $ 22.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3350595
• 关键词: atherosclerosis; autoradiography; blood lipoprotein metabolism; cell cell interaction; cell morphology; cell population study; cell type; electron microscopy; growth factor; human tissue; intercellular connection; low density lipoprotein; macrophage; membrane activity; pinocytosis; platelet derived growth factor; radiotracer; receptor mediated endocytosis; scanning electron microscopy; simian virus 40; tissue /cell culture; transforming virus; vascular endothelium; vascular smooth muscle

Atherosclerosis, the underlying cause of most human heart disease, results from a focal imbalance of the normal equilibria of the arterial wall. While metabolic cooperation between vascular cells is essential for the maintenance of normal vascular homeostasis, little is known about the nature of these interactions or whether disturbance of their equilibria will precipitate irreversible pathological changes in arterial tissue. We propose to investigate mechanisms of cellular interactions between vascular endothelium, smooth muscle cells (SMC) and monocyte-derived macrophages in vitro and in intact vascular tissue. Two separate general mechanisms of cell cooperativity will be studied: a) cell contact-mediated communication via gap junctional channels connecting the cytoplasm of adjacent cells, and b) humoral communication in which diffusible substances secreted by one cell type pass via the interstitial fluid to specific receptors on the surface of the other cell population. The effects of cell biological pertubations associated with hypercholesterolemia (cellular cholesterol, lipoprotein metabolism), a major risk factor for atherogenesis, will be investigated. New techniques to probe cellular communication in intact normal and atherosclerotic (fibrofatty lesion) vascular tissue will be tested and developed to integrate the in vitro findings with vessel wall biology and pathology. Gap junctional-mediated cell interactions will be investigated biochemically in vitro (transfer of 3H-nucleotides, fluorescent dyes and putative second messengers such as cyclic nucleotides and Ca++ and electrophysiological measurements) using cocultures of endothelial cells, SMC and macrophages. The effects of various mediators of gap junctional transfer, particularly cellular cholesterol composition, will be evaluated. The effects of heterocellular communication upon receptor-mediated lipoprotein metabolism in endothelial cells will be measured. Gap junctional communication will also be investigated in normal and atherosclerotic intact arterial tissues both at the ultrastructural level and functionally using new methods to deliver tracers to the vascular tissue. The regulation of platelet-derived growth factor-like mitogens (c-sis related) synthesized and secreted by endothelial cells will be investigated in the context of the interactions of these cells with SMC and macrophages using molecular biology techniques.

动脉粥样硬化是大多数人类心脏病的根本原因，结果 来自动脉壁正常平衡的局部不平衡。 虽然血管细胞之间的代谢合作对于 维持正常血管稳态，但人们对其知之甚少 这些相互作用的性质或它们的平衡是否受到干扰 会促使动脉组织发生不可逆的病理变化。 我们建议研究细胞之间相互作用的机制 血管内皮细胞、平滑肌细胞 (SMC) 和单核细胞来源的 体外和完整血管组织中的巨噬细胞。 两个独立的一般 将研究细胞协同性的机制：a) 细胞接触介导的 通过连接细胞质的间隙连接通道进行通讯 相邻细胞，b) 体液通讯，其中可扩散物质 由一种细胞类型分泌，通过间质液传递至特定细胞 其他细胞群表面的受体。 细胞的作用 与高胆固醇血症相关的生物扰动（细胞 胆固醇、脂蛋白代谢），是一个主要危险因素 动脉粥样硬化，将被研究。 探测细胞的新技术 完整正常和动脉粥样硬化（纤维脂肪病变）中的通讯 将测试和开发血管组织以整合体外 血管壁生物学和病理学的发现。 将研究间隙连接介导的细胞相互作用 体外生化（3H-核苷酸、荧光染料和 假定的第二信使，例如环核苷酸和 Ca++ 和 电生理测量）使用内皮细胞共培养， SMC 和巨噬细胞。 间隙连接的各种介质的影响 转移，特别是细胞胆固醇成分，将 评价。 异细胞通讯的影响 内皮细胞中受体介导的脂蛋白代谢 测量。 间隙连接通讯也将在正常情况下进行研究 和动脉粥样硬化的完整动脉组织在超微结构上 水平和功能上使用新方法将示踪剂输送到血管 组织。 血小板衍生生长因子样有丝分裂原的调节 (c-sis相关)由内皮细胞合成和分泌 在这些细胞与 SMC 相互作用的背景下进行了研究 使用分子生物学技术的巨噬细胞。