? 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.
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