Role of Arterial Calcification in Restenosis

项目摘要/摘要 美国每年进行的血管内手术超过100万例，血管内再狭窄 仍然是失败的主要原因。在动物模型中，球囊损伤后新生内膜的形成 类似于人类的再狭窄。尽管使用这个和其他模型的重大研究进展，我们有能力 将我们的知识转化为临床相关疗法尚未实现。一个因素已经越来越多地 血管内介入治疗后与加速再狭窄相关的是血管内钙化。 动脉壁。在动脉钙化过程中，中膜中的平滑肌细胞(SMC)经历表型 转化为更具骨软骨性的细胞类型。钙化的血管内皮细胞对新生内膜的影响 编队尚未进行评估。骨形态发生蛋白(BMPs)是一个信号家族 这些分子因其诱导异位骨形成的能力而被命名。我们之前已经表明， BMP4抑制SMC增殖。然而，钙化动脉中的中层细胞更类似于 在体外和体内细胞对BMP4表现出旺盛的增殖反应的发育中的骨 学习。基于这些数据，我们假设钙化动脉加速再狭窄是由于 通过一种机制促进钙化SMC的迁移、增殖和基质合成 BMP4-BMP-受体信号传导。为了验证这一假设，我们将执行以下具体目标：1) 比较BMP4在钙化和非钙化中对迁移、增殖和基质合成的影响 2)确定BMP-I受体激活是否加速了损伤诱导的新生内膜的形成 钙化动脉与未钙化动脉的比较；3)确定是否阻断BMP-I受体的激活 使用小分子抑制剂可以减少钙化动脉损伤后新生内膜的形成。为了 为了达到这些目标，我们将采取一种创新的方法--在受伤前对SMC表型进行处理 -评价动脉钙化对球囊损伤后新生内膜发育的影响。正在完成 这些目标，我们将回答一个关于钙化动脉中SMC行为的基本问题。也就是说，我们 将确定它们的成骨软骨转化是否导致它们对损伤的反应更像 比正常的SMC发育成骨。如果我们的假设是正确的，它将表明预防的疗法 再狭窄必须根据动脉壁细胞的特殊表型进行调整。此外，在这些期间， 实验我们将评估一种新型的小分子BMP抑制剂，它可能具有重要的临床意义 预防外周动脉疾病患者再狭窄的相关性。

Project Summary/Abstract Over 1,000,000 endovascular procedures are performed in the United States each year and restenosis continues to be the leading cause of failure. In animal models, neointimal development after balloon injury resembles restenosis in humans. Despite major research advances using this and other models, our ability to translate our knowledge into clinically relevant therapies has not been realized. One factor that has increasingly been associated with accelerated restenosis after endovascular interventions is the presence of calcification in the arterial wall. During arterial calcification, smooth muscle cells (SMCs) in the media undergo phenotypic transformation into a more osteochondrogenic cell type. The effects of calcifying SMCs on neointimal formation have not been assessed. The bone morphogenetic proteins (BMPs) are a family of signaling molecules that were named for their ability to induce ectopic bone formation. We have previously shown that the BMP4 inhibits SMC proliferation. Medial cells in calcified arteries, however, are more similar to those in developing bone where cells display an exuberant proliferative response to BMP4 in both in vitro and in vivo studies. Based on these data, we hypothesize that accelerated restenosis in calcified arteries occurs due to enhanced migration, proliferation, and matrix synthesis of calcifying SMCs through a mechanism involving BMP4-BMP-receptor signaling. In order to test this hypothesis, we will perform the following specific aims: 1) Compare the effects of BMP4 on migration, proliferation, and matrix synthesis in calcified versus uncalcified SMCs; 2) Determine whether BMP-receptor-I activation accelerates injury-induced neointimal development in calcified arteries compared with uncalcified arteries; 3) Determine whether blocking BMP-receptor-I activation using a small molecule inhibitor can reduce neointimal formation after injury in calcified arteries. In order to address these aims, we will take an innovative approach - manipulation of the SMC phenotype prior to injury - to evaluate the effects of arterial calcification on neointimal development after balloon injury. In completing these aims we will answer a fundamental question about the behavior of SMCs in calcified arteries. Namely, we will determine if their osteochondrogenic transformation causes them to respond to injury more like cells in developing bone than normal SMCs. If our hypothesis is correct, it will suggest that therapies to prevent restenosis must be tailored to the particular phenotype of cells in the arterial wall. Additionally, during these experiments we will evaluate a novel, small-molecule BMP inhibitor which may have significant clinical relevance for preventing restenosis in patients with peripheral artery disease.