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

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Molecular Medicine

Background:

• Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia are key drivers of atherosclerosis and post-angioplasty restenosis.
• Previous research identified TEA domain transcription factor 1 (TEAD1) as a regulator of VSMC differentiation.

Purpose of the Study:

• To investigate the role of methyltransferase-like 14 (METTL14) in vascular remodeling.
• To elucidate the molecular mechanisms by which METTL14 influences VSMC behavior and vascular pathology.

Main Methods:

• Analysis of METTL14 expression in human atherosclerotic plaques and murine carotid injury models.
• In vitro studies using human coronary artery smooth muscle cells (HCASMCs) to assess the effects of METTL14 overexpression and knockdown.
• In vivo studies involving wire-induced carotid injury in mice.
• Investigation of the m6A modification of TEAD1 mRNA and its impact on YAP1/TEAD1 signaling.

Main Results:

• METTL14 expression was upregulated in atherosclerotic arteries and correlated with VSMC dedifferentiation.
• METTL14 overexpression promoted VSMC proliferation and migration, while knockdown attenuated neointimal hyperplasia.
• METTL14 was found to stabilize TEAD1 mRNA via m6A modification at nucleotide 513, thereby enhancing YAP1/TEAD1 signaling.
• Inhibition of METTL14-mediated signaling restored VSMC differentiation and suppressed proliferation.

Conclusions:

• METTL14-mediated m6A modification of TEAD1 mRNA is a novel mechanism driving vascular pathology.
• Targeting the METTL14-TEAD1 axis presents a potential therapeutic strategy for cardiovascular diseases.