microRNA-331-3p maintains the contractile type of vascular smooth muscle cells by regulating TNF-α and CD14 in intracranial aneurysm

Abstract Dysfunction of vascular smooth muscle cells (VSMCs) may be linked to intracranial aneurysm (IA) formation. VSMCs possess a phenotypic plasticity, capable of changing from a mature, contractile to a less differentiated, synthetic phenotype. In this study, we identify a microRNA candidate miR-331-3p that participates in regulating differentiation properties of VSMCs. The expression of TNF-α and CD14 was quantified in IA wall tissues obtained from 96 IA patients and their associations with clinicopathological features of IA were assessed. Then the interactions between miR-331-3p, TNF-α and CD14 were evaluated by determination of luciferase activity. Differentiated properties of VSMCs were assessed from phenotypic markers of contractile VSMCs, a-SMA and E-cadherin, and of synthetic VSMCs, ICAM-1, MCP-1, IL-6, MMP-2 and MMP-9. Rat IA models by ligation of left carotid artery and left renal artery and histological analysis of induced IAs were performed. The TNF-α and CD14 was highly expressed in IA wall tissues and associated with the type and diameter of aneurysm. Depletion of TNF-α or CD14 retarded VSMC apoptosis and transformation to the synthetic type but facilitated cell proliferation. Elevations in miR-331-3p, a direct negative regulator of both TNF-α and CD14, also reduced VSMC apoptosis and prevented VSMCs from synthetic type and increase their proliferation. Furthermore, miR-331-3p was demonstrated to inhibit the formation of IA by down-regulating TNF-α and CD14 in vivo. In conclusion, miR-331-3p maintains the contractile type of VSMCs, thus possibly inhibiting the progression of IA. These findings provide potential new strategies for the clinical treatment of IA.