Intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) remodeling to the process. We found that cultured, early passage hCASMCs showed a high proliferation rate, sustained increases in cytosolic [Ca(2+)] in response to angiotensin II, residual voltage-operated Ca(2+) entry, increased Stim1 and enhanced store-operated currents. Non-steroidal anti-inflammatory drugs inhibited store-operated Ca(2+) 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 Ca(2+) response to angiotensin II, increased Ca(2+) store content, enhanced voltage-operated Ca(2+) entry and Cav1.2 expression, and decreases in Stim1, store-operated current and store-operated Ca(2+) entry. We conclude that proliferating hCASMCs return to quiescence and this switch is associated to a remodeling of Ca(2+) channels and their control by subcellular organelles, thus providing a window of opportunity for targeting phenotype-specific Ca(2+) channels involved in proliferation.
Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), 47003 Valladolid, Spain.
Eva
E
Muñoz
Miriam
M
Hernández-Morales
Diego
D
Sobradillo
Asunción
A
Rocher
Lucía
L
Núñez
Carlos
C
Villalobos
D000804:Angiotensin II / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008163:Luminescent Measurements; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D000071737:Stromal Interaction Molecule 1
D000893:Anti-Inflammatory Agents; D020746:Calcium Channels, L-Type; D007477:Ions; C419385:L-type calcium channel alpha(1C); D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D000804:Angiotensin II; D002118:Calcium
Mitochondria; Non-steroidal anti-inflammatory drugs; Store-operated calcium entry; Store-operated current; Vascular smooth muscle cells; Voltage-operated calcium entry