STUDIES ON ENDOTHELIUM IN RELATION TO ATHEROGENESIS

动脉粥样硬化，大多数人类心脏病的根本原因，结果 源于动脉壁正常平衡的局灶性失衡。 虽然血管细胞之间的新陈代谢合作对于 维持正常的血管内稳态，人们对此知之甚少 这些相互作用的性质或是否扰乱了它们的平衡 会导致动脉组织发生不可逆转的病变。 我们建议研究细胞间相互作用的机制 血管内皮细胞、平滑肌细胞和单核细胞来源 巨噬细胞在体外和完整的血管组织中。两个不同的将军 将研究细胞协同作用的机制：a)细胞接触介导 通过连接细胞质的缝隙连接通道进行通讯 相邻细胞，以及b)体液交流，其中可扩散的物质 由一种细胞类型分泌的物质通过间质液体传递到特定的 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)，是高血压的主要危险因素 动脉粥样硬化的形成，将被调查。探测细胞的新技术 完整的正常和动脉粥样硬化(纤维脂肪病变)中的通讯 血管组织将被测试和开发，以在体外整合 所见血管壁生物学和病理学。 将研究缝隙连接介导的细胞相互作用 体外生物化学(~3H-核苷酸、荧光染料和 推测的第二信使，如环核苷酸和钙和 电生理测量)使用内皮细胞的共培养， SMC和巨噬细胞。不同介质对缝隙连接的影响 转移，特别是细胞胆固醇的组成，将是 已评估。异质细胞通讯对生物多样性的影响 受体介导的内皮细胞脂蛋白代谢将是 量过了。缝隙连接通信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的超微结构 在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控 (C-sis相关)由内皮细胞合成和分泌的 在这些细胞与SMC和SMC相互作用的背景下进行研究 使用分子生物学技术的巨噬细胞。

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.