ACTA2 encodes α-smooth muscle actin, a critical contractile protein expressed in vascular smooth muscle cells that mediates vascular motility and contraction 1. Beyond vascular tissue, ACTA2 serves as a molecular marker for myofibroblast differentiation, where its expression in stress fibers represents an advanced functional activation state 2. During fibrotic processes, ACTA2+ cells arise from multiple sources including smooth muscle cells, endothelial cells undergoing endothelial-to-mesenchymal transition, and macrophages, with their differentiation regulated by transforming growth factor-β and platelet-derived growth factor signaling 34. Pathogenic ACTA2 variants cause multisystemic smooth muscle dysfunction syndrome, accounting for approximately 20% of familial thoracic aortic aneurysms with high dissection risk 5. Mutations induce a pathogenic phenotypic switch in smooth muscle cells from contractile to synthetic states, characterized by increased proliferation and dysregulated gene expression 6. ACTA2-associated vasculopathies manifest as diverse conditions including thoracic aortic aneurysms, dissections, premature coronary artery disease, ischemic stroke, and distinctive cerebral arteriopathy features 17. Clinically, ACTA2 mutations represent severe genetic causes of early-onset aortic disease with high mortality risk. Recent proof-of-concept studies demonstrate that CRISPR-adenine base editing can correct pathogenic ACTA2 variants, restore normal smooth muscle function, and prevent aortic dilation in preclinical models 6, suggesting potential gene-editing therapeutic approaches.