Abstract 282: Functional Analysis Of Micrornas In Vascular Disease

Abstract

microRNAs (miRNA, miR) are emerging as pivotal modulators of vascular development and disease. Research is my lab is focused on elucidating the functional mechanism and exploring therapeutic potential of microRNAs in vascular diseases. Our recent studies have shown that miR-23 and miR-27 in miR-23~27~24 family are required for proper angiogenesis and neovascularization in a laser-induced vascular injury model. Here we extend our study and provide evidence that miR-24 regulates actin dynamics in ECs through targeting multiple members downstream of Rho signaling, including Pak4, Limk2 and Diaph1 proteins. Consistent with the critical role for actin cytoskeleton in cell motility and proliferation, overexpression of miR-24 in ECs blocks stress fiber and lamellipodia formation, represses EC migration, proliferation and tube formation in vitro, as well as angiogenesis in an ex vivo aortic ring assay. Overexpression of miR-24 in transgenic mice represses postnatal retinal vascular development. Moreover, subretinal delivery of miR-24 mimics represses laser-induced CNV in vivo. Mechanistically, knockdown of miR-24 target protein LIMK2 or PAK4 inhibits stress fiber formation and tube formation in vitro, mimicking miR-24 overexpression phenotype in angiogenesis. Taken together, these findings demonstrate that miR-24 represses angiogenesis by simultaneously regulating multiple components in the actin cytoskeleton pathways, suggesting distinct function of miR-23~27~24 family members in angiogenesis. Manipulation of actin cytoskeleton pathways by miR-24 may represent an attractive therapeutic solution for numerous vascular diseases.