Abstract 5443: MicroRNA 92a Controls Vessel Growth And Functional Recovery After Ischemia
MicroRNAs (miR) are small noncoding RNAs that regulate gene expression by binding to the cellular transcript leading to translational repression or degradation of the target mRNA. So far, the impact of specific microRNAs on neovascularization and angiogenesis is widely unknown. Using a microRNA profiling, we detected several microRNAs highly expressed in endothelial cells including miR-92a. Overexpression of miR-92a significantly reduced sprouting in a spheroid model (38±6% control) and decreased capillary network formation in a matrigel assay in vitro (60±2% control).). In vivo, implanted matrigel plugs mixed with HUVECs overexpressing miR-92a showed a significantly reduced number of invaded capillary-like structures (43±7% control) and impaired perfusion (52±14% control). Inhibition of miR-92a expression in vivo by infusion of specific cholesterol-conjugated antisense molecules, so-called antagomirs, following induction of hind limb ischemia resulted in a significant reduction of tissue necrosis. Antagomir treatment further increased the recovery of blood flow (191±37%) and augmented the number of arteriols compared to scrambled controls. Likewise, infusion of antagomirs after acute myocardial infarction improved the cardiac functional recovery (dP/dt min PBS: 5903,04±403,84 mmHg/sec, Antagomir-92a: 7910,19±294,11 mmHg/sec; p=0,003; left ventricular end diastolic pressure: PBS: 16,65±1,72 mmHg, Antagomir-92a: 7,99±0,64 mmHg; p=0,001). In silico prediction revealed several regulators of endothelial functions and vessel growth such as the integrin subunits α5 and αv and the deacetylase Sirt1. Overexpression of miR-92a decreased expression of Integrin α5 (49±6%) and Sirt1 (76±11%) Furthermore, eNOS expression was significantly decreased. Consistenly, systemic administration of antagomir-92a upregulated the expression of these vasculoprotective genes in vivo. Finally, miR-92 was shown to directly target the 3′UTR of integrin α5 by using a luciferase reporter construct. These results provide key insights into the anti-angiogenic properties of miR-92a in endothelial cells and warrant further investigation of miR-92a as a putative novel therapeutic target to enhance the functional recovery of ischemic tissues.