Ultrasound shockwave therapy for post-stenotic microvascular remodeling

 描述（由申请人提供）：与高血压和外周血管疾病相关的微血管疾病在西方世界的老龄化人群中越来越常见。肾动脉阻塞远端微血管（MV）的重塑和丢失导致不可逆损伤，代谢综合征（MetS）的共存放大了这种损伤。然而，目前没有有效的临床适用的策略，能够改善MV结构和功能，恢复肾活力。低能量冲击波治疗（low-energy shock wave therapy，SWT）是一种新型的无创性实验方法，它能刺激心血管系统的生物学反应，包括刺激内源性修复能力和形成新的MV。在啮齿动物模型中，SWT可以增强内皮祖细胞（EPC）向后肢缺血部位的募集。然而，尚未研究这种新型治疗平台在与MetS相关的肾血管疾病（RVD）中改善MV活力的潜力。我们已经开发并表征了RVD和MetS的新型猪模型，这些模型允许与临床医学高度相关的转化研究，以及非常适合探测MV损伤和活力的独特成像技术。我们还显示了使用自体EPC输送到狭窄的肾动脉以改善远端功能的功效。这些工具现在提供了一个机会来测试SWT在RVD中增强肾MV功能和结构以及促进EPC募集以改善MV再生的能力。该建议的工作假设是RVD/MetS中的SWT减少损伤，改善MV活力，并促进狭窄后肾脏中循环EPC的募集。为了验证这一假设，我们将使用尖端的多探测器CT（MDCT），磁共振成像（MRI）和微型CT工具研究SWT的效果。此外，将在接受血运重建和支架植入术的PVD猪中测试SWT改善肾脏恢复前景的能力。将追求三个具体目标：具体目标1将检验SWT激活机械转导信号传导并改善与MetS相关的RVD中肾MV密度和功能的假设。具体目标2将检验这一策略将在RVD/MetS血运重建后提高肾MV活力的假设。具体目标3将检验SWT分别促进狭窄后肾脏中内源性和外源性EPC的募集和局部保留的假设。使用SWT对MV网络进行无创性改善是一种有前途的尖端技术，可能会对MV疾病的管理做出重大贡献。拟议的研究可能会产生广泛的影响，并建立这种新的，临床上可行的治疗策略RVD，代谢综合征和高血压。

 DESCRIPTION (provided by applicant): Microvascular disease associated with hypertension and peripheral vascular disease is becoming increasingly common in the aging population of the Western world. Remodeling and loss of micro vessels (MV) distal to renal arterial obstruction leads to irreversible injury, which is magnified by coexistence of the metabolic syndrome (MetS). However, no effective clinically applicable strategies are currently available that are capable of improving MV structure and function and restoring renal viability. Low-energy shock wave therapy (SWT) is a novel non-invasive experimental strategy, which elicits biological responses in the cardiovascular system, including stimulation of endogenous reparative capacity and formation of new MV. In rodent models SWT can enhance recruitment of endothelial progenitor cells (EPC) to sites of hind-limb ischemia. Yet, the potential of this novel therapeutic platform t improve MV viability in renovascular diseased (RVD) associated with MetS has not been investigated. We have developed and characterized novel swine models of RVD and MetS that allow translational studies highly relevant to clinical medicine, as well as unique imaging techniques ideally suited for probing MV injury and viability. We have also shown the efficacy of using autologous EPC delivered into a stenotic renal artery to improve distal function. These tools now afford an opportunity to test the ability of SWT to enhance renal MV function and structure in RVD and promote recruitment of EPC to improve MV regeneration. The working hypothesis underlying this proposal is that SWT in RVD/MetS decreases injury, improves MV viability, and promotes recruitment of circulating EPC in the post-stenotic kidney. To test this hypothesis, we will study the effects of SWT using cutting-edge multi-detector CT (MDCT), magnetic resonance imaging (MRI), and micro-CT tools. Furthermore, the ability of SWT to improve renal recovery prospects will be tested in PVD pigs undergoing revascularization and stenting. Three specific aims will be pursued: Specific Aim 1 will test the hypothesis that SWT activates mechano- transduction signaling and improves renal MV density and function in RVD associated with MetS. Specific Aim 2 will test the hypothesis that this tactic would boost kidney MV viability after revascularization of RVD/MetS. Specific Aim 3 will test the hypothesis that SWT promotes recruitment and local retention of endogenous and exogenous EPC, respectively, in the post-stenotic kidney. Noninvasive improvement of the MV network using SWT is a promising, cutting edge technique, which will likely contribute significantly towards management of MV disease. The proposed studies may have broad ramifications and establish this novel, clinically feasible therapeutic strategy for RVD, MetS, and hypertension.