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.

Public Health Relevance

Adequate strategies to attenuate remodeling and loss of microvessels distal to an arterial obstruction 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 can promote neovascularization, suppresses inflammation, and improves function, but is yet to be attempted in microvascular disease associated with renovascular hypertension. The proposed studies may establish this novel, clinically feasible therapeutic strategy and will likely contribute significantly towards management of patients with this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (05))
Program Officer
OH, Youngsuk
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Eirin, Alfonso; Hedayat, Ahmad F; Ferguson, Christopher M et al. (2018) Mitoprotection preserves the renal vasculature in porcine metabolic syndrome. Exp Physiol 103:1020-1029
Zou, Xiangyu; Jiang, Kai; Puranik, Amrutesh S et al. (2018) Targeting Murine Mesenchymal Stem Cells to Kidney Injury Molecule-1 Improves Their Therapeutic Efficacy in Chronic Ischemic Kidney Injury. Stem Cells Transl Med 7:394-403
Meng, Yu; Eirin, Alfonso; Zhu, Xiang-Yang et al. (2018) Obesity-induced mitochondrial dysfunction in porcine adipose tissue-derived mesenchymal stem cells. J Cell Physiol 233:5926-5936
Sun, In O; Santelli, Adrian; Abumoawad, Abdelrhman et al. (2018) Loss of Renal Peritubular Capillaries in Hypertensive Patients Is Detectable by Urinary Endothelial Microparticle Levels. Hypertension 72:1180-1188
Zhang, Xin; Zhu, Xiangyang; Ferguson, Christopher Martyn et al. (2018) Magnetic resonance elastography can monitor changes in medullary stiffness in response to treatment in the swine ischemic kidney. MAGMA 31:375-382
Aghajani Nargesi, Arash; Zhu, Xiang-Yang; Hickson, LaTonya J et al. (2018) Metabolic Syndrome Modulates Protein Import into the Mitochondria of Porcine Mesenchymal Stem Cells. Stem Cell Rev :
Ferguson, Christopher M; Eirin, Alfonso; Michalak, Gregory J et al. (2018) Intrarenal fat deposition does not interfere with the measurement of single-kidney perfusion in obese swine using multi-detector computed tomography. J Cardiovasc Comput Tomogr 12:149-152
Kim, Seo Rin; Lerman, Lilach O (2018) Diagnostic imaging in the management of patients with metabolic syndrome. Transl Res 194:1-18
Eirin, Alfonso; Textor, Stephen C; Lerman, Lilach O (2018) Emerging Paradigms in Chronic Kidney Ischemia. Hypertension 72:1023-1030
Puranik, Amrutesh S; Leaf, Irina A; Jensen, Mark A et al. (2018) Kidney-resident macrophages promote a proangiogenic environment in the normal and chronically ischemic mouse kidney. Sci Rep 8:13948

Showing the most recent 10 out of 57 publications