METTL14 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation via m6A Methylation TEAD1 mRNA

Abstract

Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia critically contribute to atherosclerosis and post-angioplasty restenosis. Building on our prior discovery that TEA domain transcription factor 1 (TEAD1) regulates VSMCs differentiation, we now investigate methyltransferase-like 14 (METTL14) in vascular remodeling. METTL14 expression was significantly upregulated in human carotid atherosclerotic plaques versus control arteries, correlating with VSMCs dedifferentiation. This pattern was recapitulated in murine wire-induced carotid injury models during neointima formation. Functionally, METTL14 overexpression suppressed contractile markers while accelerating proliferation and migration in human coronary artery smooth muscle cells (HCASMCs). Conversely, METTL14 knockdown attenuated injury-induced neointimal hyperplasia In Vivo. Mechanistically, METTL14 stabilizes TEAD1 mRNA through m6A modification at nucleotide 513, enhancing YAP1/TEAD1 signaling. Both 513nt mutation and TEAD1 inhibitor VT103 abolished METTL14-driven phenotypic changes, restoring VSMCs differentiation and suppressing proliferation. Collectively, our findings establish METTL14-mediated m6A modification of TEAD1 mRNA as a novel mechanism promoting vascular pathology, highlighting its therapeutic potential for cardiovascular diseases.