Intracellular Ca2+ remodeling during the phenotypic journey of human coronary smooth muscle cells

Abstract

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 Cav1.2 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.