Mechanisms of Collateral Arteriogenesis in Ischemia

描述(申请人提供)：本项目的目的是提高我们对缺血时动脉形成的理解。这一过程，包括先前存在的小动脉吻合的外向重塑和新的或“新的侧支”的形成，目前还不是很清楚。此外，许多缺血性疾病患者在侧支发育方面表现出缺陷。已经鉴定出一种在动脉结扎后严重缺乏血流灌注恢复的小鼠品系，但造成这种损害的原因尚不清楚。目的应用我们开发的新的动脉生成成像方法，介绍一种研究新生侧支形成的新策略，并验证新侧支形成存在缺陷的假说。有证据表明，在损伤和/或重塑过程中，介导早期血管发育的形态发生途径Sonic hedgehog-notch在成人中可能重新激活。这一途径在动脉形成中的作用尚未被研究。我们的初步数据表明，Shh信号在侧支成熟过程中起着重要作用。因此，AIM II将检验这样一种假设，即Shh-Noch信号有助于先前存在的侧支成熟和新侧支的形成，并且在受损品系中它是有缺陷的。

DESCRIPTION (provided by applicant): The purpose of this project is to improve our understanding of arteriogenesis in ischemia. This process, consisting of outward remodeling of pre-existing arteriole anastomoses and formation of new or "neo-collaterals", is not well understood. Moreover, many patients with ischemic disease show a deficit in collateral development. A mouse strain with a severe deficiency in recovery of perfusion after artery ligation has been identified, but the reasons for the impairment are unknown. Aim I will use new methods we have developed for imaging arteriogenesis, will introduce a new strategy for study of neo-collateral formation, and will test the hypothesis that formation of neo-collaterals is defective in the strain. There is evidence that the morphogenic pathway, Sonic hedgehog-notch, which mediates early vascular development, may be reactivated in adults during injury and/or remodeling. A role for this pathway in arteriogenesis has not been studied. Our preliminary data suggest Shh signaling is important in collateral maturation. Therefore, Aim II will examine the hypothesis that Shh-notch signaling contributes to pre-existing collateral maturation and neo-collateral formation, and that it is defective in the impaired strain.