Endothelial Progenitor Cells Restore Renal Function in Chronic Experimental Renovascular Disease

Abstract

Background-Endothelial progenitor cells (EPCs) promote neovascularization and endothelial repair. Renal artery stenosis (RAS) may impair renal function by inducing intrarenal microvascular injury and remodeling. We investigated whether replenishment with EPCs would protect the renal microcirculation in chronic experimental renovascular disease. Methods and Results-Single-kidney hemodynamics and function were assessed with the use of multidetector computed tomography in vivo in pigs with RAS, pigs with RAS 4 weeks after intrarenal infusion of autologous EPCs, and controls. Renal microvascular remodeling and angiogenic pathways were investigated ex vivo with the use of micro-computed tomography, histology, and Western blotting. EPCs increased renal expression of angiogenic factors, stimulated proliferation and maturation of new vessels, and attenuated renal microvascular remodeling and fibrosis in RAS. Furthermore, EPCs normalized the blunted renal microvascular and filtration function. Conclusions-The present study shows that a single intrarenal infusion of autologous EPCs preserved microvascular architecture and function and decreased microvascular remodeling in experimental chronic RAS. It is likely that restoration of the angiogenic cascade by autologous EPCs involved not only generation of new vessels but also acceleration of their maturation and stabilization. This contributed to preserving the blood supply, hemodynamics, and function of the RAS kidney, supporting EPCs as a promising therapeutic intervention for preserving the kidney in renovascular disease. (Circulation. 2009;119:547-557.)Key Words: blood flow Ⅲ kidney Ⅲ progenitor cells Ⅲ renal artery stenosis Ⅲ hypertension, renal E ndothelial progenitor cells (EPCs) mobilized endogenously in response to ischemia play a crucial role in augmenting neovascularization of ischemic tissues and endothelial replacement after vascular injury. Replenishment of such cells may limit vascular injury through reconstitution of the luminal barrier and cellular secretion of paracrine factors, providing a novel therapeutic option. 1,2 Indeed, growing experimental and clinical evidence underscores the critical role that circulating cells play in healing the endothelium when the intrinsic system is unable to adequately support tissue repair. Targeted delivery of EPCs has been shown to improve the function of the infarcted myocardium, 3 decrease hindlimb ischemia, 4,5 rescue the kidney from acute ischemia injury, 6 and participate in glomerular endothelial repair in glomerulonephritis. 7 Clinical Perspective p 557Ischemic nephropathy secondary to renal artery stenosis (RAS) represents an important cause of renovascular disease and hypertension that may induce renal injury and lead to end-stage renal disease. The presence of renovascular disease also constitutes an independent predictor for increased morbidity and mortality in cardiovascular disease and cardiac events. 8 We have shown previously that the kidney exposed to chronic RAS shows significant functional deteriorati...

Cell-Based Therapies as an Adjunct to Revascularization in Experimental Atherosclerotic Reno Vascular Disease

“…Their mobilization from bone marrow and recruitment to the injured kidney is regulated by the release of homing factors such as stromal cell-derived factor (SDF)-1 and stem cell factor (SCF). Our group has demonstrated that delivery of EPC in the stenotic ARVD kidney improved renal hemodynamic and function and decreased the release of endogenous injury signals from the stenotic kidney [15,16]. In line with these observations, we have shown in swine ARVD that intra-renal delivery of autologous hematopoietic EPC during PTRA improved renal hemodynamics and function in the post-stenotic kidney [17].…”

TGF Expression and Macrophage Accumulation in Atherosclerotic Renal Artery Stenosis

“…Such injury may respond to alternative or adjunctive interventions to modify repair pathways independent of large vessel hemodynamics. As an example, recent studies using endothelial progenitor cells in experimental ARAS demonstrate restoration of both microvascular structures and GFR using cell-based therapy (40). Furthermore, delivery of adipose-derived mesenchymal stem cells in conjunction with revascularization of experimental ARAS demonstrate anti-inflammatory potential and improved efficacy of revascularization (41).…”

Rapid Anastomosis of Endothelial Progenitor Cell–Derived Vessels with Host Vasculature Is Promoted by a High Density of Cotransplanted Fibroblasts

“…For example, transplanted EPCs have been shown to induce angiogenesis and restore the function of ischemic tissue. 21,22 Importantly, like other ECs, EPCs can form robust vessel networks in engineered tissue constructs in the presence of stromal cells, and can be functional in vivo for up to 28 days. [17][18][19] However, a study addressing the critical issue of the rate of anastomosis using engineered vessels formed by EPCs has yet to be reported.…”