Role of Arterial Calcification in Restenosis

项目总结/摘要 在美国每年进行超过1，000，000例血管内手术， 仍然是失败的主要原因。在动物模型中，球囊损伤后的新生内膜发展 类似于人类的再狭窄。尽管使用这种模型和其他模型的研究取得了重大进展，但我们的能力， 将我们的知识转化为临床相关疗法还没有实现。一个因素是， 与血管内介入后加速再狭窄相关的是血管内钙化的存在。 动脉壁在动脉钙化过程中，中膜平滑肌细胞（SMC）发生表型改变， 转化成更多的骨软骨细胞类型。钙化平滑肌细胞对新生内膜的影响 没有评估形成。骨形态发生蛋白（BMPs）是一个信号传导家族， 这些分子因其诱导异位骨形成的能力而命名。我们之前已经证明， BMP 4抑制SMC增殖。然而，钙化动脉中的中膜细胞与 发育中的骨，其中细胞在体外和体内均显示出对BMP 4的旺盛增殖反应 问题研究基于这些数据，我们假设钙化动脉的加速再狭窄是由于 通过一种机制增强钙化SMC的迁移、增殖和基质合成， BMP 4-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BMP 4在钙化与非钙化中对迁移、增殖和基质合成的影响。 2）确定BMP-受体-I激活是否加速了SMC中损伤诱导的新生内膜发育。 钙化动脉与非钙化动脉比较; 3）确定阻断BMP-受体-I激活是否 使用小分子抑制剂可以减少钙化动脉损伤后的新生内膜形成。为了 为了实现这些目标，我们将采取一种创新的方法--在损伤前操纵SMC表型 - 评价动脉钙化对球囊损伤后新生内膜形成的影响。在完成 这些目标，我们将回答一个基本的问题，平滑肌细胞的行为在钙化动脉。即，我们 将确定它们的骨软骨形成转化是否会导致它们对损伤的反应更像细胞， 比正常的SMCs发育骨。如果我们的假设是正确的，这将表明， 再狭窄必须适应动脉壁中细胞的特定表型。此外，在这些 我们将评估一种新的小分子BMP抑制剂， 与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.