Epigenetic Reprogramming via TET2 Prevents Medial Calcification and Restores Vascular Smooth Muscle Cell Identity

Vascular calcification arises from the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and is a hallmark of many cardiovascular pathologies. This study identifies Tet2, a DNA demethylase, as a critical epigenetic regulator that prevents this phenotypic switch. VSMC-specific loss of Tet2 promotes osteogenic differentiation, apoptosis, increased infiltration of Trem2^hi macrophages and medial aortic calcification. High-dose ascorbate used to enhance Tet2 activity significantly reduced calcification and preserved aortic structure in mice. These findings support Tet2 reactivation as a potential therapeutic strategy to prevent or reverse vascular calcification in cardiovascular disease.