MicroRNA-145 Restores Contractile Vascular Smooth Muscle Phenotype and Coronary Collateral Growth in the Metabolic Syndrome

Objective-Transient, repetitive occlusion stimulates coronary collateral growth (CCG) in normal animals. Vascular smooth muscle cells (VSMCs) switch to synthetic phenotype early in CCG, then return to contractile phenotype. CCG is impaired in the metabolic syndrome. We determined whether impaired CCG was attributable to aberrant VSMC phenotypic modulation by miR-145-mediated mechanisms, and whether restoration of physiological miR-145 levels in metabolic syndrome (JCR rat) improved CCG. Approach and Results-CCG was stimulated by transient, repetitive left anterior descending artery occlusion and evaluated after 9 days by coronary blood flow measurements (microspheres). miR-145 was delivered to JCR VSMCs via adenoviral vector (miR-145-Adv). In JCR rats, miR-145 was decreased late in CCG (approximate to 2-fold day 6; approximate to 4-fold day 9 versus SD), which correlated with decreased expression of smooth muscle-specific contractile proteins (approximate to 5-fold day 6; approximate to 10-fold day 9 versus SD), indicative of VSMCs' failure to return to the contractile phenotype late in CCG. miR-145 expression in JCR rats (miR-145-Adv) on days 6 to 9 of CCG completely restored VSMCs contractile phenotype and CCG (collateral/normal zone flow ratio was 0.93 +/- 0.09 JCR+miR-145-Adv versus 0.12 +/- 0.02 JCR versus 0.87 +/- 0.02 SD). Conclusions-Restoration of VSMC contractile phenotype through miR-145 delivery is a highly promising intervention for restoration of CCG in the metabolic syndrome. (Arterioscler Thromb Vasc Biol. 2013; 33: 727-736.)