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Ca²⁺ source-dependent transcription of CRE-containing genes in vascular smooth muscle

¹Department of Pharmacology, ²Totman Center for Cerebrovascular Research, ³Department of Microbiology and Molecular Genetics, ⁴Department of Biology, and ⁵Department of Surgery, Division of Neurological Surgery, University of Vermont, Burlington, Vermont

Submitted 15 July 2005 ; accepted in final form 1 February 2006

Altered Ca²⁺ handling has immediate physiological and long-term genomic effects on vascular smooth muscle function. Previously we showed that Ca²⁺ entry through voltage-dependent Ca²⁺ channels (VDCCs) or store-operated Ca²⁺ channels (SOCCs) results in phosphorylation of the Ca²⁺/cAMP response element (CRE)-binding protein in cerebral arteries. Here, oligonucleotide array analysis was used to determine gene transcription profiles resulting from these two Ca²⁺ entry pathways in human cerebrovascular smooth muscle cell cultures. Results were confirmed and expanded using quantitative RT-PCR, Western blot, and immunofluorescence. A distinct, yet overlapping, set of CRE-regulated genes was induced by VDCC activation using K⁺ membrane depolarization vs. SOCC activation by thapsigargin (TG). Membrane depolarization selectively induced a sustained increase in early growth response-1 (Egr-1) mRNA and protein, which were inhibited by the VDCC blocker nimodipine and the SOCC inhibitor 2-aminoethoxydiphenylborate (2-APB). TG selectively induced a sustained increase in MAPK phosphatase-1 (MKP-1) mRNA and protein, and these effects were decreased by 2-APB, but not by nimodipine. The physiological agonist ANG II also stimulated expression of Egr-1 and MKP-1. Coadministration of 2-APB prevented expression of Egr-1 and MKP-1, whereas nimodipine blocked only Egr-1 expression. TG and ANG II induced phosphorylation of ERK, which was sensitive to 2-APB and was selectively required for CRE-binding protein phosphorylation. Our findings thus indicate that Ca²⁺ entry through VDCCs and store-operated Ca²⁺ entry can differentially regulate CRE-containing genes in vascular smooth muscle and also imply that agonist-induced signals involved in modulation of gene transcription can be controlled by multiple sources of Ca²⁺.

microarray; calcium signaling; arterial remodeling; vascular smooth muscle cell proliferation

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