Regulation of vascular smooth muscle cell proliferation by plasma membrane Ca2+-ATPase

We have previously shown that reductions in c-Myb-dependent transcription inhibit cell cycle progression and decrease intracellular Ca2+ concentrations in vascular smooth muscle cells (VSMC). We now report that these effects are largely mediated by a 4- to 10-fold increased rate of La3+-sensitive Ca-45 extrusion, which is associated with 2- to 4-fold increased levels of plasma membrane Ca2+-ATPase 1 (PMCA1) mRNA and protein. PMCA4 mRNA, present at much lower concentrations, undergoes similar changes during suppression of c-Myb activity. We also report that PMCA1 expression is regulated during VSMC cell cycle progression, such that levels of PMCA1 are 40% lower at the G(1)/S interface than at Go. Moreover, transient overexpression of PMCA1a in VSMC elevates the Ca-45 efflux rate by similar to 2-fold, decreases resting and peak thapsigargin-releasable Ca2+ concentrations at G(1)/S by 43% (68 nM) and 52% (160 nM), respectively, and reduces the rate of cell proliferation by over 2.5-fold. These data define a mechanism for c-Myb-dependent Ca2+ homeostasis and support a critical role for PMCA in the regulation of VSMC growth.