Hybrid Imaging of Angiogenesis and Arteriogenesis

描述（申请人提供）：外周动脉疾病（PAD）是困扰8- 1200万美国人的主要临床问题，并导致严重的死亡和残疾。靶向药物或遗传疗法可通过经由现有侧支动脉的血管重塑（动脉生成）和/或通过刺激增加的微血管密度（血管生成）改善灌注来提供这些患者的临床改善。这些生物学过程之间存在重要的相互关系，然而，血管生成或动脉生成是否是生理改善的主要介质仍不确定。我们将表征这些过程的相互作用，特别是使用完善的后肢缺血小鼠模型来定义avb 3整联蛋白和一氧化氮（NO）在介导缺氧诱导的血管生成和流动诱导的动脉生成中的作用。目前的建议是一个有竞争力的更新项目，以前针对开发的非侵入性放射性示踪剂为基础的成像策略，以确定缺氧刺激血管生成，并直接评估血管生成使用放射性示踪剂靶向的avb 3整合素。当前项目的主要目标是使用非侵入性混合microSPECT/X射线CT成像策略应用和改进这些方法，用于体内评估血管生成和动脉生成在PAD中的相互依赖作用，并探索NO的作用在调节介导这些过程的细胞上表达的整合素。我们假设缺血可能通过调节几种细胞类型上的整合素介导血管生成过程，并且由此导致的组织灌注增加和血管阻力降低导致流量介导的动脉生成增加。该项目将利用已建立的选择性结合avb 3整合素的靶向放射性示踪剂，沿着放射性示踪剂将跟踪与血管生成和动脉生成相关的组织灌注和缺氧的生理变化。混合microSPECT/CT成像系统不仅允许生物图像与发育中的血管结构的共配准，而且便于示踪剂摄取的量化。目前的应用直接建立在以前开发的新型成像方法的基础上，并将利用已建立的缺血和血流诱导的血管生成模型来研究血管生成和动脉生成的关键机制，这对PAD患者的评估和管理具有潜在的重要临床意义。

DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) is a major clinical problem afflicting 8-12 million Americans, and causes significant mortality and disability. Targeted medical or genetic therapies might provide clinical improvement of these patients through improved perfusion via vascular remodeling of existing collateral arteries (arteriogenesis) and/or by stimulating increased microvascular density (angiogenesis). There is an important interrelationship between these biological processes, however, it remains uncertain whether angiogenesis or arteriogenesis is the principal mediator of physiological improvement. We will characterize the interplay of these processes, in particular defining the role of avb3 integrins and nitric oxide (NO) in mediating hypoxia- induced angiogenesis and flow-induced arteriogenesis using well established murine models of hindlimb ischemia. The current proposal is a competitive renewal of a project previously directed at development of non-invasive radiotracer-based imaging strategies for identification of the hypoxic stimulus for angiogenesis, and direct evaluation of angiogenesis using radiotracers targeted at the avb3 integrin. A principal goal of the current project is to apply and refine these methodologies using non-invasive hybrid microSPECT/X-ray CT imaging strategies for the in vivo evaluation of the interdependent roles of angiogenesis and arteriogenesis in PAD, and to explore the role of NO in the regulation of integrins expressed on cells that mediate these processes. We hypothesize that ischemia may mediate the angiogenic process through regulation of integrins on several cell types, and that the resulting increases in tissue perfusion and decreases in vascular resistance result in increased flow-mediated arteriogenesis. The project will take advantage of established targeted radiotracers that selectively bind to the avb3 integrin, along with radiotracers that will track physiological changes in tissue perfusion and hypoxia associated with angiogenesis and arteriogenesis. The hybrid microSPECT/CT imaging system not only permits co-registration of biological images with developing vascular structures but facilitates quantification of tracer uptake. The current application builds directly on the novel imaging approaches previously developed, and will take advantage of established models of ischemia- and flow-induced angiogenesis to the study a critical mechanism of angiogenesis and arteriogenesis with potentially important clinical implications for evaluation and management of patients with PAD.