Hybrid Imaging of Angiogenesis and Arteriogenesis

描述（由申请人提供）：外周动脉疾病（PAD）是困扰800 - 1200万美国人的主要临床问题，并导致大量死亡和残疾。有针对性的药物或基因治疗可以通过现有侧支动脉的血管重塑（动脉生成）和/或通过刺激微血管密度增加（血管生成）来改善灌注，从而改善这些患者的临床状况。这些生物过程之间存在着重要的相互关系，然而，血管生成或动脉生成是否是生理改善的主要媒介仍不确定。我们将描述这些过程的相互作用，特别是定义avb3整合素和一氧化氮（NO）在缺氧诱导的血管生成和血流诱导的动脉生成中的作用，使用完善的小鼠后肢缺血模型。目前的提案是一个竞争性的项目更新，先前的项目旨在开发基于无创放射性示踪剂的成像策略，用于识别缺氧刺激血管生成，并使用靶向avb3整合素的放射性示踪剂直接评估血管生成。当前项目的主要目标是应用和完善这些方法，使用非侵入性混合显微spect / x射线CT成像策略来评估PAD中血管生成和动脉生成的相互依赖作用，并探索NO在调节细胞上表达的整合素介导这些过程中的作用。我们假设缺血可能通过对几种细胞类型的整合素的调节来介导血管生成过程，从而导致组织灌注的增加和血管阻力的降低，从而导致血流介导的动脉生成增加。该项目将利用已建立的靶向放射性示踪剂，选择性地结合avb3整合素，以及放射性示踪剂，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。混合显微spect /CT成像系统不仅允许生物图像与发育中的血管结构共同配准，而且促进了示踪剂摄取的量化。目前的应用直接建立在先前开发的新成像方法的基础上，并将利用已建立的缺血和血流诱导血管生成模型来研究血管生成和动脉生成的关键机制，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.