ARTERY WALL CONTRACTION, WOUND HEALING, AND RESTENOSIS

动脉重建后的动脉管腔再狭窄仍然存在 动脉粥样硬化治疗中的一个主要问题。它的作用机制 重建后的动脉管腔狭窄并不明确。 最近的证据，特别是来自血管内超声的证据， 这表明再狭窄的传统观点认为是由于管腔 侵占内膜生长是错误的。相反，看起来 管腔大小可以通过动脉壁直径的变化来确定，或者 改建。我们最近从一个血管成形术模型中获得的数据 动脉粥样硬化的非人类灵长类支持管腔的这种机制 狭窄并提示动脉壁未能重塑和 扩张以适应内膜生长，是 血管再狭窄。 我们提出两种假设来解释损伤后的室壁收缩。 动脉粥样硬化。首先，管腔变窄可能是由于相同的原因 伤口愈合过程中出现的各种组织收缩。已创建的裂缝 血管成形术可以通过类似的机制收缩，即相互作用 在收缩细胞、整合素和细胞外基质之间。 第二，酶在细胞外基质中的重要程度 降解(金属蛋白酶)在损伤的动脉中表达。 墙可能决定墙的改型能力。动脉具有 金属蛋白酶活性降低可能降低重塑的能力 以应对血管内膜的生长，导致再狭窄。 这些假说将在动脉粥样硬化的非人类灵长类动物中进行探索。 正在接受血管成形术。我们已经收集了一些来自 此模型中血管成形术的先前研究。这些组织将被用来 广泛地表征结构、组织学和生化 与损伤后管腔狭窄相关的变量。中的更改 管腔大小将与整合素的表达进行比较，整合素的基质 可能在室壁重塑中发挥作用的配体和金属蛋白酶。 新的动物研究将直接解决组织的机制 靶向阻断实验对重塑的收缩作用 整合素。动物将用一种特异性封闭抗体进行治疗 用于血管成形术时的avbeta3整合素。管腔口径将 通过定量血管造影术来确定管腔的程度 缩小范围。组织学、形态学和血管造影术的终点 对这些动脉进行测量，以确定它们在血管壁中的作用 改建。整合素阻断对金属蛋白酶的影响 表达和活性将被评估并与管腔狭窄相关， AS整合素信号通路在其调控中起着重要作用。 这些研究将进一步加深我们对结构基础的理解 动脉粥样硬化性动脉再狭窄，并可识别不同的 预防性治疗的分子靶点。

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.