DESCRIPTION (provided by applicant): Peripheral vascular disease (PVD) is becoming increasingly common in the aging population of the Western world. Renovascular hypertension (RVH) associated with large vessel PVD induces remodeling and loss of downstream microvessels (MV), which are often irreversible after restoration of vascular patency. Alas, adequate strategies to restore the microcirculation and improve outcomes in RVH and PVD are yet to be identified and remain in dire need. Non-invasive low-energy extracorporeal shock wave treatment (SWT) is a novel experimental strategy, which generates mechanical forces that exert localized stress on cell membranes and elicit biological responses in the cardiovascular and musculoskeletal systems, including suppression of inflammation and stimulation of new MV formation. Remarkably, the potential of this novel approach to protect the microcirculation in chronic RVH and increase MV viability has not been explored. We have developed and characterized novel swine models of RVH that closely mimic human pathophysiology. Furthermore, we have developed and refined unique imaging techniques ideally suited for probing MV adaptive processes in PVD, as well as their potential contribution to MV injury and viability. These tools now provide a unique opportunity to assess the effects of low-energy extracorporeal SWT on pathophysiology and outcomes in RVH, and the feasibility of modifying them with novel interventions. The working hypothesis underlying this proposal is that SWT in RVH-PVD is safe, and would decrease MV injury, improve function and oxygenation, and thereby improve recovery upon restoration of upstream vascular patency. To test this hypothesis, we will study the effects of SWT utilizing a combination of cutting- edge multi-detector CT (MDCT), magnetic resonance imaging (MRI), and micro-CT using innovative tools. Furthermore, the ability of SWT to improve renal recovery prospects will be tested in PVD pigs undergoing revascularization and stenting. Two specific aims will be pursued: Specific Aim 1 will test the hypothesis that SWT is safe, and would improve function and structure distal to vascular obstruction 4 weeks later. Specific Aim 2 will test the hypothesis that SWT would restore the recovery potential of the kidney in response to revascularization of PVD. The proposed studies will advance our understanding of the pathogenesis of MV injury distal to PVD, and may establish a novel, clinically feasible therapeutic strategy. Improvement of the MV network is a promising technique in cardiovascular medicine, but this cutting edge approach is yet to be applied in RVH-PVD. Thus, these studies will likely contribute significantly towards management of PVD.
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