Objectives: 

Abnormal proliferation of vascular smooth muscle cells, a process related to ion channel remodeling, contribute to occlusive disorders including restenosis and atherosclerosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent VSMC proliferation and occlusive disorders by an unknown mechanism. We aimed at characterizing the role of calcium channel remodeling in the reversal phenotypic switch of cultured human coronary artery smooth muscle cells (hCASMCs) and the antiproliferative mechanism of NSAIDs.

Materials: 

For this end we used cytosolic and mitochondrial calcium imaging and electrophysiological recordings in addition to real-time PCR and western blotting.

Results: 

We found that early passage hCASMCs showed a proliferating phenotype, proliferation depending fully on store-operated calcium entry (SOCE), but not on voltage-operated calcium entry (VOCE). Proliferating hCASMCs showed large SOCE, SOCE-induced mitochondrial calcium uptake and Stim1 whereas VOCE was residual. NSAIDs inhibited SOCE as well as proliferation and migration. After a few passages hCASM cells switched to a non proliferating phenotype characterized by decreased SOCE and Stim1 and increased VOCE, Cav1.2 and VOCE-induced mitochondrial calcium uptake. NSAIDs failed to inhibit SOCE in the non-proliferating cells.

Conclusions: 

We conclude that proliferating hCASMCs undergo a reversal phenotypic switch in culture towards quiescent cells mediated by remodeling of calcium channels that may reflect the changes underlying vascular occlusive disorders. NSAIDs inhibit SOCE and hCASMC proliferation and migration in a mitochondria-dependent, phenotypic specific manner.

This work was funded by DIGICYT (BFU2009-08967) and Junta de Castilla y León, Spain (VA270A11-2). EM and DS were supported by predoctoral fellowships from FPI (DIGICYT) and JAE (CSI) programs, respectively.