Invited commentary

Abstract

Critical limb ischemia is a complex multifactorial disease with limited treatment options. The pathophysiologic mechanism of critical limb ischemia is one of underlying inflammation elaborated by a variety of cells including neutrophils, macrophages, lymphocytes, and cytokines. More recently, investigation into means of modulating angiogenesis and arteriogenesis through the use of endogenous small noncoding RNAs (microRNAs) has been described. MicroRNAs have been thought to have a role in angiogenesis as well as being modulators of vascular inflammation. The authors of this manuscript have conducted experiments using a mouse model of hindlimb ischemia by femoral ligation and local delivery of microRNA-126 (miR-126) through poly lactic-co-glycolic acid (PLGA) nanoparticles as a vehicle to assess the angiogenic effects of local sustained release of miR-126. They show increased perfusion by laser Doppler imaging and increased capillary and arteriolar density in animals treated with miR-126-loaded PLGA nanoparticles. They believe that miR-126 exerts its effect in part through downstream effectors in the vascular endothelial growth factor receptor pathway through SPRED1. The most important finding of this study is identification of a reliable delivery vehicle for targeted microRNA. As the authors comment, they have not demonstrated what effect, if any, the drug delivery system mediated by PLGA has on the vasculature as no administration of PLGA alone was performed. Further experiments will also be performed on animal models of atherosclerosis to quantify functional end points, including walking distance, to elucidate the clinical relevance of miR-126. This study effectively highlights the complexity of the pathogenesis of limb ischemia and mechanisms used to compensate when the ischemia is acute. A genetic background may not play as important a role as risk factors, including smoking, hypertension, and hyperlipidemia, in the development of limb ischemia. The line of investigation proposed by the authors of this manuscript is important, as studies to date identifying molecules that appear to ameliorate critical limb ischemia have thus far not been effective in mitigating the human disease process. Therapeutic angiogenesis by local sustained release of microRNA-126 using poly lactic-co-glycolic acid nanoparticles in murine hindlimb ischemiaJournal of Vascular SurgeryVol. 68Issue 4PreviewRecent studies demonstrate that microRNAs show promising potential, including angiogenesis, in therapeutic intervention. MicroRNA-126 (miR-126) is reported to regulate angiogenesis by blocking Sprouty-related EVH1 domain-containing protein 1 (SPRED1), an endogenous inhibitor of vascular endothelial cell growth factor. In this study, we investigated the angiogenic effects of the sustained release of miR-126 loaded with poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) in a murine hindlimb ischemia model. Full-Text PDF Open Archive