Neovascularization Driven by MicroRNA Delivery to the Endothelium

Atherosclerotic disease can lead to severely debilitating conditions, such as myocardial infarction and peripheral artery disease, which are associated with poorly perfused tissue. Despite the initial promise of proangiogenic gene therapy or cell-based approaches to rectify ischemic diseases in preclinical models,1–3 large randomized placebo-controlled clinical trials have revealed only modest effects, at best.4,5 Alternatively, rather than delivering proangiogenic genes (such as vascular endothelial growth factor [ VEGF ]) or proangiogenic cells, manipulating pathways that lie downstream of receptors for angiogenic factors may provide a more robust outcome. In this regard, microRNAs (miRs) are appealing as therapeutic targets/agents for several reasons: (1) miRs often repress multiple targets within common or complementary pathways, allowing for a strong synergistic effect that is less likely to induce resistance compared with a single therapeutic target, (2) miRs are short ≈22 nucleotide sequences that can be easily inhibited or overexpressed, and (3) miR sequences are highly conserved across multiple species, aiding the transition between preclinical animal models and clinical trials in humans.6See accompanying article on page 2401 Extensive research has revealed that miR-126-3p, an endothelium-enriched miR, promotes angiogenesis and vascular stability by targeting distinct repressors (ie, sprouty-related, EVH1 domain containing 1 [SPRED1] and phosphatidylinositol 3-kinase regulatory subunit 2 [PIK3R2]) of the VEGF pathway.7–10 Interestingly, miR-126 delivery to endothelial cells (ECs) via circulating microparticles or apoptotic bodies promotes vascular repair in animal models,11,12 providing a strong impetus to develop miR-126–directed proangiogenic therapies. One of the major challenges in using miRs as a therapeutic is the difficulty in limiting delivery to the appropriate cell type or tissue. Although therapeutic delivery of miRs to ECs has recently …