ARTERY WALL CONTRACTION, WOUND HEALING, AND RESTENOSIS

动脉壁收缩、伤口愈合和再狭窄

• 批准号: 2463154
• 负责人: Randolph L. Geary
• 金额: $ 27.22万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2463154
• 关键词: Macaca fascicularis; artery stenosis; atherosclerosis; biological signal transduction; enzyme activity; gene expression; histogenesis; immunocytochemistry; in situ hybridization; integrins; intraluminal angioplasty; metalloendopeptidases; muscle contraction; protein structure function; tissue /cell culture; tissue inhibitor of metalloproteinases; vascular smooth muscle; wound healing

Restenosis of the artery lumen following arterial reconstruction remains a major problem in the treatment of atherosclerosis. The mechanisms of artery lumen narrowing following reconstruction are poorly defined. Recent evidence, particularly that from intravascular ultrasound, suggests that the traditional view of restenosis as being due to lumen encroachment from intimal growth is wrong. Rather, it appears that lumen size may be determined by changes in artery wall diameter, or remodeling. Our recent data from a model of angioplasty in atherosclerotic nonhuman primates support this mechanism of lumen narrowing and suggest that failure of the artery wall to remodel and enlarge to accommodate intimal growth, is a central component of restenosis. We propose two hypotheses to explain wall contraction in injured atherosclerotic arteries. First, lumen narrowing may be due to the same kinds of tissue contraction seen during wound healing. Fractures created by angioplasty may contract by an analogous mechanism, an interplay among contractile cells, integrins and the extracellular matrix. Second, the degree to which enzymes important in extracellular matrix degradation (metalloproteinases) are expressed within the injured artery wall may determine the capacity of the wall to remodel. Arteries with decreased metalloproteinase activity may be less capable of remodeling in response to intimal growth, resulting in restenosis. These hypotheses will be explored in atherosclerotic nonhuman primates undergoing angioplasty. We have collected a number of arteries from previous studies of angioplasty in this model. These tissue will be used to extensively characterize structural, histological and biochemical variables associated with lumen narrowing after injury. Changes in lumen size will be compared to expression of integrins, their matrix ligands and metalloproteinases which may play a role in wall remodeling. New animal studies will directly address the mechanism of tissue contraction in remodeling through targeted blocking experiments of integrins. Animals will be treated with a blocking antibody specific for the avbeta3 integrin at the time of angioplasty. Lumen caliber will be assessed by quantitative angiography to determine the degree of lumen narrowing. Histological, morphological and angiographic end points will be measured in these arteries to determine their role in wall remodeling. The effects of integrin-blockade on metalloproteinase expression and activity will be assessed and related to lumen narrowing, as integrin signaling pathways are important in their regulation. These studies will further our understanding of the structural basis of restenosis in atherosclerotic arteries and may identify distinct molecular targets for preventive therapy.

动脉重建后的动脉腔恢复 动脉粥样硬化治疗中的主要问题。 的机制 重建后的动脉腔狭窄定义不明确。 最近的证据，特别是血管内超声， 表明再狭窄的传统观点是由于管腔 内膜生长的侵入是错误的。 相反， 管腔尺寸可以通过动脉壁直径的变化来确定，或者 重塑 我们最近的数据来自一个血管成形术模型， 动脉粥样硬化的非人类灵长类动物支持这种管腔机制 并表明动脉壁重塑失败， 扩张以适应内膜生长，是 再狭窄 我们提出两种假设来解释受伤时的室壁收缩 动脉粥样硬化 首先，管腔狭窄可能是由于相同的 在伤口愈合过程中看到的各种组织收缩。创建的骨折 通过血管成形术可以通过类似的机制收缩， 在收缩细胞、整合素和细胞外基质中。 第二，在细胞外基质中重要的酶 降解（金属蛋白酶）在损伤的动脉内表达 墙可以决定墙的改造能力。 动脉与 降低的金属蛋白酶活性可能不太能够重塑 从而导致再狭窄。 这些假设将在动脉粥样硬化的非人灵长类动物中进行探讨 接受血管成形术 我们收集了一些动脉， 在此模型中进行血管成形术的先前研究。这些组织将用于 以广泛表征结构、组织学和生物化学 与损伤后管腔狭窄相关的变量。 变化 将管腔大小与整合素、其基质 配体和金属蛋白酶可能在壁重塑中起作用。 新的动物研究将直接解决组织的机制 通过靶向阻断实验， 整合素 动物将接受特异性封闭抗体治疗 血管成形术时的α v β 3整合素。管腔口径将 通过定量血管造影术进行评估，以确定管腔程度 缩小 组织学、形态学和血管造影终点将 在这些动脉中进行测量，以确定它们在壁中的作用 重塑 整合素阻断剂对金属蛋白酶的影响 将评估表达和活性并将其与管腔变窄相关， 因为整联蛋白信号通路在其调节中是重要的。 这些研究将进一步加深我们对 动脉粥样硬化动脉再狭窄， 预防性治疗的分子靶点。