Regulation of Smooth Muscle Contractility by Competing Endogenous mRNAs in Intracranial Aneurysms

Abstract

Alterations in vascular smooth muscle cells (SMCs) contribute to the pathogenesis of intracranial aneurysms (IAs), but the genetic mechanisms underlying these alterations are unclear. We used microarray analysis to compare tissue small noncoding RNA and messenger RNA expression profiles in vessel wall samples from patients with late-stage IAs. We identified myocardin (MYOCD), a key contractility regulator of vascular SMCs, as a critical factor in IA progression. Using a multifaceted computational and experimental approach, we determined that depletion of competitive endogenous RNAs (ARHGEF12, FGF12, and ADCY5) enhanced factors that downregulate MYOCD, which induces the conversion of SMCs from differentiated contractile states into dedifferentiated phenotypes that exhibit enhanced proliferation, synthesis of new extracellular matrix, and organization of mural thrombi. These effects may lead to the repair and maintenance of IAs. This study presents guidelines for the prediction and validation of the IA regulator MYOCD in competitive endogenous RNA networks and facilitates the development of novel therapeutic and diagnostic tools for IAs.