Intracellular Ca remodeling during the phenotypic journey of human coronary smooth muscle cells

Vascular smooth muscle cells undergo phenotypic switches after damage which may contribute to proliferative disorders of the vessel wall. This process has been related to remodeling of Ca²⁺ channels. We have tested the ability of cultured human coronary artery smooth muscle cells (hCASMCs) to return from a proliferative to a quiescent behavior and the contribution of intracellular Ca²⁺ remodeling to the process. We found that cultured, early passage hCASMCs showed a high proliferation rate, sustained increases in cytosolic [Ca²⁺] in response to angiotensin II, residual voltage-operated Ca²⁺ entry, increased Stim1 and enhanced store-operated currents. Non-steroidal anti-inflammatory drugs inhibited store-operated Ca²⁺ entry and abolished cell proliferation in a mitochondria-dependent manner. After a few passages, hCASMCs turned to a quiescent phenotype characterized by lack of proliferation, oscillatory Ca²⁺ response to angiotensin II, increased Ca²⁺ store content, enhanced voltage-operated Ca²⁺ entry and Ca_v1.2 expression, and decreases in Stim1, store-operated current and store-operated Ca²⁺ entry. We conclude that proliferating hCASMCs return to quiescence and this switch is associated to a remodeling of Ca²⁺ channels and their control by subcellular organelles, thus providing a window of opportunity for targeting phenotype-specific Ca²⁺ channels involved in proliferation.