Ultrasound shockwave therapy for post-stenotic microvascular remodeling

 描述(申请人提供)：与高血压和周围血管疾病相关的微血管疾病在西方世界老龄化的人口中变得越来越常见。肾动脉梗阻远端微血管(MV)的重构和丢失会导致不可逆转的损伤，代谢综合征(METS)的存在会放大这种损伤。然而，目前还没有有效的临床适用的策略，能够改善MV的结构和功能，恢复肾脏活力。低能量冲击波治疗(SWT)是一种新的非侵入性实验策略，它在心血管系统中引起生物反应，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可促进内皮祖细胞(EPC)在后肢缺血部位的募集。然而，这一新的治疗平台在提高甲硫氨酸相关性肾血管病(RVD)患者MV存活率方面的潜力尚未得到研究。我们已经开发并鉴定了新的RVD和METS猪模型，这些模型允许进行与临床医学高度相关的转译研究，以及非常适合探测MV损伤和生存能力的独特成像技术。我们还展示了在狭窄的肾动脉内使用自体内皮祖细胞来改善远端功能的效果。这些工具现在提供了一个机会，以测试SWT在RVD中增强肾脏MV功能和结构的能力，并促进EPC的募集以促进MV再生。支持这一建议的工作假设是，RVD/Mets中的SWT减少了损伤，提高了MV的存活率，并促进了狭窄后肾脏循环内皮祖细胞的募集。为了验证这一假设，我们将使用尖端多探测器CT(MDCT)、磁共振成像(MRI)和微型CT工具来研究SWT的效果。此外，SWT改善肾脏恢复前景的能力将在接受血管重建和支架植入的PVD猪身上进行测试。将追求三个具体目标：特定目标1将验证SWT激活机械转导信号并改善METS相关RVD的肾MV密度和功能的假设。具体目标2将验证这样的假设，即在RVD/METS血运重建后，这种策略将提高肾脏MV的存活率。具体目标3将检验SWT促进内源性和外源性EPC在狭窄后肾脏中的募集和局部保留的假设。利用SWT对MV网络进行无创性改良是一种很有前途的尖端技术，可能会对MV疾病的治疗做出重大贡献。拟议的研究可能会产生广泛的影响，并建立这一新的、临床上可行的治疗RVD、METS和高血压的策略。

 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.