Mitogen-induced p53 downregulation precedes vascular smooth muscle cell migration from healthy tunica media and proliferation

The tumor suppressor protein p53 plays an important role in the cell-cycle G(1) and G(2) checkpoints. In response to DNA damage, p53 can induce the tr anscription of p21, which inhibits the activation of various G(1) cyclin/cy clin-dependent kinase complexes. It is not known whether p53 plays a role i n the initial migration of vascular smooth muscle cells from the arterial t unica media (mVSMCs). In this study, we have investigated whether mVSMC mig ration from healthy tunica media of young pigs and proliferation are regula ted by p53. After 6 hours of incubation in mitogen-rich medium, explanted p orcine tunica media tissue showed complete downregulation of p53 protein an d p53 mRNA. The blockage of gene activity was not due to DNA methylation at the 5' control region of the gene. The mVSMC outgrowth did not show p53 ex pression. Mitogen-depletion of cultured p53(-)/mVSMCs did not restore p53 e xpression. Incubation of explanted porcine tunica media tissue in mitogen-d eprived medium increased p53 protein content and blocked mVSMC outgrowth fr om the explant. As in p53-deficient rodent cells, mVSMCs incubated with col cemid overrode the spindle-dependent checkpoint, giving polyploidy and chro mosomal pairing. UV-induced DNA damage in mVSMCs incubated with mitogen-fre e medium induced p53 expression and apoptotic cell death showing DNA nucleo somal laddering. However, UV-irradiated mVSMCs incubated in mitogen-rich me dium did not express p53 and did not show cell death. In conclusion, our re sults demonstrate that early mVSMC migration from the tunica media requires mitogen-induced suppression of p53 that is highly expressed in contractile mVSMCs residing in the healthy vessel wall.