Role of arterial calcification in restenosis

描述（由申请人提供）：美国每年进行超过1，000，000例血管内手术，再狭窄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，但我们将知识转化为临床相关疗法的能力尚未实现。与血管内介入术后再狭窄加速相关的一个因素是动脉壁钙化的存在。在动脉钙化期间，中膜中的平滑肌细胞（SMC）经历表型转化为更具骨软骨形成性的细胞类型。尚未评估钙化SMC对新生内膜形成的影响。骨形态发生蛋白（BMPs）是一个信号分子家族，因其诱导异位骨形成的能力而命名。我们以前已经表明，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中的中膜细胞更相似，在体外和体内研究中，骨中的细胞对BMP 4显示出旺盛的增殖反应。基于这些数据，我们假设钙化动脉中再狭窄的加速发生是由于钙化SMC通过涉及BMP 4-BMP受体信号传导的机制增强了迁移、增殖和基质合成。为了验证这一假设，我们将进行以下具体目标：1）比较BMP 4对钙化与未钙化SMC中的迁移、增殖和基质合成的影响; 2）确定BMP-受体-I活化是否加速钙化动脉与未钙化动脉中损伤诱导的新生内膜发育; 3）确定使用小分子抑制剂阻断BMP-受体-I活化是否可以减少钙化动脉损伤后的新生内膜形成。为了实现这些目标，我们将采用一种创新的方法--损伤前对SMC表型的处理--来评价球囊损伤后动脉钙化对新生内膜发育的影响。在完成这些目标的过程中，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，我们将确定它们的骨软骨形成转化是否使它们对损伤的反应更像发育中的骨细胞而不是正常的SMC。如果我们的假设是正确的，这将表明，治疗，以防止再狭窄必须量身定制的特定表型的细胞在动脉壁。此外，在这些实验中，我们将评估一种新的，小分子BMP抑制剂，这可能有显着的临床意义，预防再狭窄患者外周动脉疾病。 公共卫生相关性：血管成形术通常由于再狭窄而失败，再狭窄是在动脉内部形成的病理性瘢痕。在血管疾病患者中，动脉钙化是再狭窄的强有力预测因素。在这个建议中，我们将研究为什么钙化的动脉容易发生再狭窄。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Angioplasty procedures commonly fail due to restenosis which is a pathologic scarring that develops on the inside of arteries. In patients with vascular disease, arterial calcification is a strong predictor of restenosis. In this proposal, we will study why calcified arteries are prone to develop restenosis.