Cell Cycle Dependent Regulation of Intracellular Calcium Concentration in Vascular Smooth Muscle Cells: A Potential Target for Drug Therapy

Intracellular Ca2+ transients have been shown to control several transition points within the eukaryotic cell cycle. We focus here on the G1-to-S phase transition triggered by an increase in the intracellular Ca2+ concentration {[Ca2+]i } in rodent vascular smooth muscle cells {VSMC} and its potential targeting for the treatment of vaso-occlusive processes such as atherosclerosis, hypertension and post-angioplasty restenosis.The transcription factor c-Myb generates a G1 / S transition-specific Ca2+ transient via its regulation of a high affinity Ca2+ efflux pump, the plasma membrane Ca2+ ATPase-1 {PMCA1}. Two c-Myb binding sites in the PMCA1 promoter mediate the cell cycle-associated repression of PMCA1. As c-Myb levels increase in late G1 phase of proliferating VSMC, transcription from the PMCA1 promoter is reduced, expression of the PMCA1 gene falls, and the resultant reduced rate of Ca2+ efflux underlies a G1 / S-associated increase in [Ca2+]i . Blocking either the upregulation of c-Myb levels, or the down regulation in expression of the efflux pump, leads to significant reductions in S phase entry and proliferation of VSMC. A search for functional c-Myb sites within the promoters of other Ca2+ transporters has been undertaken in order to extend the molecular framework of the G1 / S-specific Ca2+ signal mediated by the c-Myb transcription factor.Animal studies with c-myb antisense oligodeoxynucleotides and an anti-c-myb ribozyme as well as in vitro results with dominant negative c-Myb mutants and a doxycycline-inducible c-Myb neutralizing antibody point to the potential of c-Myb-targeted gene therapy for treating pathologic VSMC proliferation and highlight the need for clinical trials in this field.