Role of progesterone on the regulation of vascular muscle cells proliferation, migration and apoptosis

Abstract

The purpose of this study was to investigate the effect of progesterone (Pg) on cellular growth, migration, apoptosis, and the molecular mechanism of action displayed by the steroid. To that end, rat aortic vascular smooth muscle cell (VSMC) cultures were employed. Pg (10 nM) significantly increased [3H]thymidine incorporation after 24 h of treatment. The enhancement in DNA synthesis was blunted in the presence of an antagonist of Pg receptor (RU486 compound). The mitogenic action of the steroid was suppressed by the presence of the compounds PD98059 (MEK inhibitor), chelerythrine (PKC inhibitor), and indomethacin (cyclooxygenase antagonist) suggesting that the stimulation of DNA synthesis involves MAPK, PKC, and cyclooxygenase transduction pathways. The proliferative effect of the hormone depends on the presence of endothelial cells (EC). When muscle cells were incubated with conditioned media obtained of EC treated with Pg, the mitogenic action of the steroid declined. Wounding assays shows that 10 nM Pg enhances VSMC migration and motility. The role of the steroid on programmed cell death was measured using DNA fragmentation technique. Four hours of treatment with 10 nM Pg enhanced DNA laddering in a similarly extent to the apoptotic effect induced by the apoptogen hydrogen peroxide (H2O2). In summary the results presented provide evidence that Pg enhances cell proliferation, migration, and apoptosis of VSMC. The modulation of cell growth elicited by the steroid involves integration between genomic and signal transduction pathways activation.