Role of arterial calcification in restenosis

描述(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育类似于人类的再狭窄。尽管使用这一模型和其他模型取得了重大研究进展，但我们将知识转化为临床相关疗法的能力尚未实现。血管内介入治疗后加速再狭窄的一个因素是动脉壁钙化的存在。在动脉钙化过程中，基质中的平滑肌细胞(SMC)经历表型转化为更具骨软骨性的细胞类型。钙化的SMC对新生内膜形成的影响还没有被评估。骨形态发生蛋白(BMPs)是一类信号分子，因其具有诱导异位成骨的能力而得名。我们先前已经证明BMP4抑制SMC的增殖。然而，钙化动脉中的中层细胞更类似于发育中的骨中的细胞，在体外和体内的研究中，这些细胞对BMP4都表现出旺盛的增殖反应。基于这些数据，我们假设钙化动脉的加速再狭窄是由于钙化的SMC通过涉及BMP4-BMP受体信号的机制促进了迁移、增殖和基质合成而发生的。为了验证这一假说，我们将执行以下特定目标：1)比较BMP4对钙化和非钙化SMC迁移、增殖和基质合成的影响；2)确定与未钙化动脉相比，BMP-I受体激活是否加速了损伤诱导的钙化动脉新生内膜的形成；3)确定使用小分子抑制剂阻断BMP-I受体激活是否可以减少钙化动脉损伤后新生内膜的形成。为了达到这些目标，我们将采用一种创新的方法--损伤前对SMC表型的处理--来评估动脉钙化对球囊损伤后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，我们将确定它们的成骨转化是否导致它们对损伤的反应更像发育中的骨骼中的细胞，而不是正常的SMC。如果我们的假设是正确的，这将表明预防再狭窄的治疗必须针对动脉壁细胞的特定表型而量身定做。此外，在这些实验中，我们将评估一种新型的小分子BMP抑制剂，它可能对预防外周动脉疾病患者的再狭窄具有重要的临床意义。 公共卫生相关性：血管成形术通常会因为再狭窄而失败，再狭窄是一种在动脉内部形成的病理性疤痕。在血管疾病患者中，动脉钙化是再狭窄的强烈预测指标。在这项提案中，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.