Bioengineered VEGF Therapy Following Angioplasty in Renovascular Disease: More and Better Microvessels

Abstract

Asymmetric dimethylarginine (ADMA) is a pro‐atherogenic marker of endothelial dysfunction and inhibitor of endothelial nitric oxide synthase (eNOS) that may contribute to progression of renal injury. We designed a novel bioengineered fusion of an elastin‐like polypeptide with vascular endothelial growth factor (ELP‐VEGF). We showed that ELP‐VEGF therapy in renovascular disease (RVD) restores renal hemodynamics by improving microvascular (MV) rarefaction in the stenotic kidney. Our preliminary data suggest that co‐adjuvant ELP‐VEGF therapy with renal angioplasty (PTRAs) enhances renal recovery compared to PTRAs alone. We aimed to elucidate underlying mechanisms of renoprotection and test the hypothesis that co‐adjuvant ELP‐VEGF+PTRAs decreases ADMA and thus, its effects on eNOS inhibition, causing augmented renal bioavailability of NO and improvements of MV endothelial function, renal hemodynamics, and reversal of MV rarefaction.RVD was induced by unilateral renal artery stenosis and high cholesterol feeding in 14 pigs. Six weeks later, single‐kidney blood flow (RBF) and filtration (GFR) were quantified in vivo using multi‐detector CT at baseline and during an endothelium‐dependent challenge (with acetylcholine, Ach). Then pigs were randomized to either PTRAs+placebo or PTRAs followed by intra‐renal ELP‐VEGF therapy (RVD+PTRAs+ELP‐VEGF). Pigs were observed for four additional weeks; in vivo CT studies repeated, then pigs were euthanized, and ex vivo renal MV micro‐CT quantification, plasma ADMA concentration, and stenotic kidney eNOS, VEGF, and Flk‐1 expression were measured.Pre‐treatment renal hemodynamics were equally reduced and PTRAs similarly resolved renal artery stenosis in all pigs with RVD. However, PTRAs+ELP‐VEGF led to significantly greater recovery of RBF and GFR and responses to Ach than PTRAs alone. Improvements in renal function were accompanied by decreased plasma ADMA and enhanced stenotic kidney expression of eNOS, VEGF, and its Flk‐1 receptor, and improved MV density and remodeling (Figure).This study extends our previous findings by identifying a potential mechanism of enhanced renal recovery after combined PTRAs+ELP‐VEGF therapy. Reductions in circulating ADMA may have contributed to the improved renal expression of eNOS in tandem with VEGF therapy, resulting in augmented renal bioavailability of NO and ultimately improving functional and structural renal MV rarefaction. Furthermore, decreased ADMA may suggest a slowing down of the atherosclerotic process in the RVD kidney, which may have also helped contribute to the greater improvements in MV density and overall renal function after PTRAs+ELP‐VEGF therapy.Support or Funding InformationR41DK109737, R01HL095638, P01HL51971, P20GM104357, R01HL121527, EIA18490005, IPA34170267, and T32HL105324This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.