Cadmium Sulphate Induces Pro-Atherogenic Phenotypic Switching in Human Aortic Smooth Muscle Cells

Background & Objectives: Vascular smooth muscle cells (VSMCs) maintain vascular integrity but can transition from a quiescent, contractile phenotype to a synthetic, migratory, and proliferative state, a critical driver of atherosclerosis. Cadmium, a persistent and bioaccumulative environmental toxicant, common in cigarette smoke and industrial emissions, has been epidemiologically associated with coronary artery disease; however, its mechanistic effects on VSMC behavior remain unclear. This study investigated whether cadmium sulphate (CdSO₄) promotes phenotypic switching in human aortic smooth muscle cells (HASMCs) and examined associated molecular and functional consequences. Methods: HASMCs (ATCC) were cultured under standard conditions and exposed to graded concentrations of CdSO₄. Cytotoxicity and metabolic activity were assessed using the CCK-8 assay to determine sub-toxic exposure ranges. Based on viability profiling, three concentrations (1 µM, 15 µM, 25 µM) were selected for mechanistic analyses. Phenotypic switching was evaluated by quantitative polymerase chain reaction (qPCR) analysis of contractile markers (ACTA2, TAGLN), osteogenic marker (BMP2), and inflammatory marker (CD68). Functional alterations were assessed using the scratch wound migration assay and Ki-67 immunostaining to evaluate cellular proliferation. Results: CdSO₄ exposure induced significant phenotypic modulation in HASMCs characterized by upregulation of BMP2 and CD68, accompanied by marked downregulation of ACTA2 and TAGLN, indicating loss of contractile identity and acquisition of osteogenic and inflammatory features. Sub-toxic cadmium exposure significantly increased cell migration and proliferation, consistent with a synthetic, pro-atherogenic phenotype. Conclusions: CdSO₄ promotes pro-atherogenic phenotypic switching and functional activation of HASMCs, providing mechanistic evidence linking cadmium exposure to vascular remodeling and atherosclerosis, and reinforce the importance of mitigating heavy metal exposure to prevent cardiovascular disease burden.