NO inhibits arterial injury after vascular procedures via adventitial stem cells

NO 通过外膜干细胞抑制血管手术后的动脉损伤

• 批准号: 8454509
• 负责人: Melina Rae Kibbe
• 金额: $ 36.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-11 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454509
• 关键词: Affect; Angioplasty; Arterial Injury; Biology; Blood Vessels; Bone Marrow; Bypass; CD34 gene; Cell Proliferation; Cells; Cellular Infiltration; Cellularity; Coculture Techniques; Collagen; Data; Development; Endarterectomy; Excision; Exposure to; Failure; Fibroblast Growth Factor 2; Fibroblasts; Fibronectins; Granulocyte Colony-Stimulating Factor; Growth; Hyperplasia; Hypoxia; In Vitro; Inflammatory; Injury; Intervention; Lead; Mediating; Mediator of activation protein; Mus; Myofibroblast; Nitric Oxide; Pericytes; Platelet-Derived Growth Factor; Population; Procedures; Process; Production; Reactive Oxygen Species; Recruitment Activity; Relative (related person); Research; Role; Smooth Muscle Myocytes; Starvation; Stem cells; Stimulus; Time; Tunica Adventitia; Vascular Endothelial Growth Factors; cell type; density; in vivo; inhibitor/antagonist; innovation; intima media; loss of function; macrophage; migration; novel; overexpression; prevent; public health relevance; research study; response; response to injury; restenosis; stem; trafficking

DESCRIPTION (provided by applicant): Neointimal hyperplasia is a significant problem that results in the failure of vascular interventions. The classic arterial injury response that leads to the development of neointimal hyperplasia describes processes involving the intima and media with a relative lack of involvement of the adventitia. However, the adventitia is no longer considered a simple structural component of the arterial wall. In the last decade, research has shown that many cell types from the adventitia actively regulate and contribute to the development of neointimal hyperplasia, including resident and circulating adventitial stem and progenitor cells. We, and others, have demonstrated that NO is a potent inhibitor of neointimal hyperplasia through regulating different aspects of the classic arterial injury response. However, little is known about how NO affects the adventitial layer of the arterial wall following injury. We have recently assessed the cellular response throughout the arterial wall to injury and exposure to NO. Interestingly, while NO prevents the development of neointimal hyperplasia and delays repopulation of the media, we were surprised to find that NO actually increases cellularity in the adventitia. This increase in cellularity is not due to an increase in vascular smooth muscle cells, fibroblasts, myofibroblasts, or inflammatory cells, but may in fact be due to an increase in Sca1+ progenitor cells, among others. Thus, given the important role of the adventitia in regulating the arterial injury response, recent discoveries of the role of stem and progenitor cells in this process, and our preliminary data, we hypothesize that NO inhibits neointimal hyperplasia by regulating recruitment and phenotypic differentiation of resident and circulating adventitial stem and progenitor cells following injury. Furthermore, we hypothesize that NO supports differentiation of adventitial stem and progenitor cells into endothelial-like cells, contributing to adventitial neovascularity. To investigate these hypotheses, our specific aims are: 1) to characterize the effect of NO on Sca1+, CD34+, and flk-1+ adventitial stem and progenitor cell populations following arterial injury in vivo; 2) to determine the effect of NO on Sca1+, CD34+, and flk-1+ adventitial cell populations in vitro; and 3) to manipulate Sca1+, CD34+, and flk-1+ adventitial cell populations in vivo to determine if NO-mediated inhibition of neointimal hyperplasia following arterial injury is dependent on these adventitial cell populations. The innovative studies described in this proposal will result in a change in how we think about the adventitia and the vascular biology of NO, and provide a novel mechanism by which NO regulates neointimal hyperplasia that will lead to the development of new strategies to prevent neointimal hyperplasia and restenosis following vascular interventions.

描述（由申请人提供）：新生内膜增生是导致血管干预失败的重要问题。导致新内膜增生的经典动脉损伤反应描述了涉及内膜和中膜的过程，而相对缺乏对外膜的累及。然而，外膜不再被认为是动脉壁的简单结构组成部分。在过去的十年中，研究表明许多来自外膜的细胞类型积极调节和促进新生内膜增生的发展，包括常驻和循环外膜干细胞和祖细胞。我们和其他人已经证明，通过调节经典动脉损伤反应的不同方面，NO是一种有效的内膜增生抑制剂。然而，关于NO在损伤后如何影响动脉壁外皮层，我们知之甚少。我们最近评估了整个动脉壁对损伤和暴露于NO的细胞反应。有趣的是，虽然NO可以阻止新生内膜增生的发展并延迟介质的再生，但我们惊讶地发现NO实际上增加了外膜的细胞数量。细胞数量的增加不是由于血管平滑肌细胞、成纤维细胞、肌成纤维细胞或炎症细胞的增加，而实际上可能是由于Sca1+祖细胞等的增加。因此，考虑到外膜在调节动脉损伤反应中的重要作用，以及干细胞和祖细胞在这一过程中的作用的最新发现，以及我们的初步数据，我们假设NO通过调节损伤后常驻和循环外膜干细胞和祖细胞的募集和表型分化来抑制新内膜增生。此外，我们假设一氧化氮支持内皮干细胞和祖细胞向内皮样细胞的分化，促进了内皮新生血管的形成。为了研究这些假设，我们的具体目标是：1)表征NO对体内动脉损伤后Sca1+、CD34+和flk-1+上皮干细胞和祖细胞群的影响；2)体外测定NO对Sca1+、CD34+和flk-1+外体细胞群的影响；3)在体内操纵Sca1+、CD34+和flk-1+外内膜细胞群，以确定no介导的动脉损伤后内膜增生的抑制是否依赖于这些外内膜细胞群。本提案所描述的创新研究将改变我们对NO外膜和血管生物学的看法，并提供NO调节新内膜增生的新机制，这将导致开发新的策略来预防血管干预后的新内膜增生和再狭窄。