Abstract 13102: Microrna-150 Modulates Ischemia-induced Neovascularization in Atherosclerotic Conditions

Abstract

Background: Hypercholesterolemia is an atherosclerotic condition that is associated with impaired neovascularization in response to ischemia. This study sought to define the role of microRNAs (miRNAs) in that pathophysiology. Methods and results: Next generation sequencing and qRT-PCR analyses identified miR-150 as a pro-angiogenic miRNA which expression is significantly reduced in the ischemic muscles of hypercholesterolemic ApoE-deficient (ApoE -/- ) mice, and in HUVECs exposed to oxLDL. Forced expression of miR-150 using a miR mimic could rescue oxLDL-mediated impairment of endothelial cell migration and tubule formation in vitro. In a mouse model of hindlimb ischemia, intramuscular injection of miR-150 mimic restored blood flow recuperation, vascular densities in ischemic muscles, and functional mobility in ApoE -/- mice. Treatment of ApoE -/- mice with miR-150 also increased the number and the activities of pro-angiogenic cells (PACs). miR-150 targets SRC kinase signaling inhibitor 1 (SRCIN1), an important regulator of Src activity. Here we found that hypercholesterolemia and oxLDL exposure are associated with increased SRCIN1 expression and decreased Src activity. However, treatment with miR-150 mimic reduces SRCIN1 expression and restores Src and downstream eNOS and Akt activities both in vitro and in vivo. We also demonstrate that the angiogenic effects of miR-150 are abolished when endothelial cells are treated with an inhibitor of Src. Conclusions: Hypercholesterolemia is associated with reduced expression of miR-150, impaired Src signaling and inefficient neovascularisation in response to ischemia. Forced expression of miR-150 using a miR mimic could constitute a novel therapeutic strategy to improve ischemia-induced neovascularization in atherosclerotic conditions.