Journal
CIRCULATION RESEARCH
Volume 86, Issue 7, Pages 760-767Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.86.7.760
Keywords
Ca2+ sparks; CREB; gene expression; receptors, ryanodine; arterial smooth muscle
Funding
- NHLBI NIH HHS [HL44455] Funding Source: Medline
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Pathological changes of the vasculature are characterized by changes in Ca2+ handling and alterations in gene expression. In neurons and other cell types, [Ca2+](i) often drives changes in gene expression. However, the relationship between Ca2+ signaling and gene expression in vascular smooth muscle is not well understood. This study examines the ability of Ca2+ influx through voltage-dependent, L-type Ca2+ channels (VDCCs) and Ca2+ release through ryanodine receptors (RyRs) to activate the transcription factor, cAMP-responsive element binding protein (CREB), and increase c-fos levels in intact cerebral arteries. Membrane depolarization increased the fraction of nuclei staining for phosphorylated CREB (P-CREB) and levels of c-fos mRNA in intact mouse cerebral arteries. Ryanodine, which inhibits RyRs, increased P-CREB staining and c-fos levels. Forskolin, an activator of adenylyl cyclase, and sodium nitroprusside, an NO donor, increased P-CREB and c-fos levels. Nisoldipine, an inhibitor of VDCCs, reversed the effects of depolarization and ryanodine on P-CREB and c-fos levels, but not the effects of forskolin or sodium nitroprusside. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaM kinase) blocked increases in P-CREB and c-fos levels seen with membrane depolarization, suggesting that CaM kinase has an important role in the pathway leading from Ca2+ influx to CREB-mediated changes in c-fos levels. Our data suggest that membrane depolarization increases [Ca2+], through activation of VDCCs, leading to increased P-CREB and c-fos, and that RyRs have a profound effect on this pathway by indirectly regulating Ca2+ entry through VDCCs. These results provide the first evidence of Ca2+ regulation of CREB and c-fos in arterial smooth muscle.
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