Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity

1,25 dihydroxyvitamin D3 (1,25 (OH)2 D) and its less hypercalcemic analogues have been shown to inhibit the proliferation of vascular smooth muscle cells (VSMC) in culture. However, the mechanism(s) underlying this suppression is not well understood. Here we have shown that 1,25 (OH)2 D and its analogues (RO-25-6760 and RO-23-7553) inhibit endothelin (ET)-dependent DNA synthesis and cell proliferation in neonatal rat aortic VSMC. While ET stimulation of mitogenic activity requires activation of the MEK/ERK signal transduction cascade, 1,25 (OH)2 D neither affected the ET-dependent activation of ERK nor synergized with the MEK inhibitor PD98059 in reducing DNA synthesis in these cultures, implying that the locus of 1,25 (OH)2 D actions lies between ERK and the cell cycle machinery. 1,25 (OH)2 D suppressed ET-induced activation of cyclin-dependent kinase 2 (Cdk2), a key cell cycle kinase, but had no effect on the expression of this protein. Collectively, the data identify Cdk2 as the target of 1,25 (OH)2 D in the cell cycle machinery and imply a potential role for 1,25 (OH)2 D, or its less hypercalcemic analogues, in the treatment of disorders of VSMC proliferation involving the vascular wall.