Store-Operated Ca 2+ Entry Activates the CREB Transcription Factor in Vascular Smooth Muscle

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Abstract
Ca 2+ -regulated gene transcription is a critical component of arterial responses to injury, hypertension, and tumor-stimulated angiogenesis. The Ca 2+ /cAMP response element binding protein (CREB), a transcription factor that regulates expression of many genes, is activated by Ca 2+ -induced phosphorylation. Multiple Ca 2+ entry pathways may contribute to CREB activation in vascular smooth muscle including voltage-dependent Ca 2+ channels and store-operated Ca 2+ entry (SOCE). To investigate a role for SOCE in CREB activation, we measured CREB phosphorylation using immunofluorescence, intracellular Ca 2+ levels using a fluorescence resonance energy transfer (FRET)–based Cameleon indicator, and c-fos transcription using RT-PCR. In this study, we report that SOCE activates CREB in both cultured smooth muscle cells and intact arteries. Depletion of intracellular Ca 2+ stores with thapsigargin increased nuclear phospho-CREB levels, intracellular Ca 2+ concentration, and transcription of c-fos . These effects were abolished by inhibiting SOCE through lowering extracellular Ca 2+ concentration or by application of 2-aminoethoxydiphenylborate and Ni 2+ . Inhibition of Ca 2+ influx through voltage-dependent Ca 2+ channels using nimodipine partially blocked intact artery responses, but was without effect in cultured smooth muscle cells. Our findings indicate that Ca 2+ entry through store-operated Ca 2+ channels leads to CREB activation, suggesting that SOCE contributes to the regulation of gene expression in vascular smooth muscle.