Endogenous Regulators of Plaque Angiogenesis

描述(申请人摘要)：人类和其他人的动脉粥样硬化病变 这种疾病的动物模型与血管增多的区域有关 增殖并延伸至内膜层的血管。已发布的数据 提示这些斑块毛细血管可能是细胞增殖的标志，促进 炎性细胞进入病变，或可能参与斑块出血 以及可能引发心肌梗死或中风的破裂。在最近 研究表明，血管内皮细胞抑制物可减少血管内膜新生和 载脂蛋白E基因缺陷小鼠的斑块生长，提示斑块血管生成 有助于动脉粥样硬化的进展。由于它与 疾病进展和急性缺血性并发症的发展，它是 与了解机制和识别内生因素有关 调节斑块血管生成的物质。 载脂蛋白E-/-进展期病变内膜新生血管已被记录 老鼠。动脉粥样硬化病变将在无血清体外试验中进行检测 斑块诱导萌发以表征相关生物学特性 刺激病变血管生成的活动。APOE-/-小鼠将得到治疗 用这些内源性因子的特定拮抗剂来确定它们是否 在体内调节斑块血管生成和病变生长。内皮抑素和 内源性血管生成抑制物保留在血管内侧层 大动脉。APOE-/-小鼠将与胶原蛋白缺陷小鼠杂交 XV11/Endostatjn以确定是否丢失内源性抑制物 主动脉血管生成将增强血管内膜新生血管和斑块 成长。不同血管生成抑制剂治疗动脉粥样硬化病变 将进行评估，以确定这些制剂在 病变的细胞含量和周转率。

DESCRIPTION (Applicant's abstract): Atherosclerotic lesions in humans and other animal models of the disease are associated with areas of increased vasa vasasorum that proliferate and extend into the intimal layer. Published data suggests these plaque capillaries may be markers of cell proliferation, promote inflammatory cell entry into lesions, or may be involved in plaque hemorrhage and rupture that can initiate a myocardial infarction or stroke. In recent studies, endotheljal cell inhibitors reduced intimal neovascularization and plaque growth in ApoE-deficient mice, which suggest plaque angiogenesis contributes to the progression of atherosclerosis. Due to its association with disease progression and the development of acute ischemic complications, it is relevant to understand the mechanisms and to identify the endogenous factors that regulate plaque angiogenesis. Intimal neovascularization has been documented in advanced lesions of ApoE-/- mice. Atherosclerotic lesions will be tested in a serum-free in vitro assay of plaque-induced sprout formation to characterize the relative biologic activities that stimulate angiogenesis in lesions. ApoE-/- mice will be treated with specific antagonists of these endogenous factors to determine if they regulate plaque angiogenesis and lesion growth in vivo. Endostatin an endogenous inhibitor of angiogenesis is retained in the medial layer of the aorta. ApoE-/- mice will be crossed with mice deficient in collagen XVlll/endostatjn to determine if loss of an endogenous inhibitor of angiogenesis in the aorta will enhance intimal neovascularization and plaque growth. Atherosclerotic lesions treated with different angiogenesis inhibitors will be evaluated to determine the functional consequences of these agents on the cell content and turnover of lesions.