Mitogen-Induced p53 Downregulation Precedes Vascular Smooth Muscle Cell Migration From Healthy Tunica Media and Proliferation

Abstract

Abstract-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 transcription of p21, which inhibits the activation of various G 1 cyclin/cyclindependent kinase complexes. It is not known whether p53 plays a role in the initial migration of vascular smooth muscle cells from the arterial tunica media (mVSMCs). In this study, we have investigated whether mVSMC migration from healthy tunica media of young pigs and proliferation are regulated by p53. After 6 hours of incubation in mitogen-rich medium, explanted porcine tunica media tissue showed complete downregulation of p53 protein and p53 mRNA. The blockage of gene activity was not due to DNA methylation at the 5Ј control region of the gene. The mVSMC outgrowth did not show p53 expression. Mitogen-depletion of cultured p53 Ϫ /mVSMCs did not restore p53 expression. Incubation of explanted porcine tunica media tissue in mitogen-deprived medium increased p53 protein content and blocked mVSMC outgrowth from the explant. As in p53-deficient rodent cells, mVSMCs incubated with colcemid overrode the spindle-dependent checkpoint, giving polyploidy and chromosomal pairing. UV-induced DNA damage in mVSMCs incubated with mitogen-free medium induced p53 expression and apoptotic cell death showing DNA nucleosomal laddering. However, UV-irradiated mVSMCs incubated in mitogen-rich medium did not express p53 and did not show cell death. In conclusion, our results 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.

Effects of Panax notoginseng saponins on proliferation and apoptosis of vascular smooth muscle cells

“…and vasoactive substances. In response to multiple stimuli, VSMCs in the arterial media are activated, and subsequently migrate to and proliferate in the intima, which seem to be early steps in the formation of atherosclerosis (Rodriguez-Campos et al, 2001). Until recently, VSMCs have been viewed as directly responsible for generating the atherosclerotic plaque via proliferation and synthesis of matrix proteins in the intima.…”

Effect of p53 Deficiency on External Vascular Cuff-Induced Neointima Formation.

“…28 Finally, there is a classical hypothesis that proposes that medial smooth muscle cells change their phenotype and migrate to the subendothelial space where they proliferate, thus generating the neointima. Because VSMC migration and proliferation occur after the downregulation of its p53, 6 the absence of p53 could lead to the accumulation of medial smooth muscle cells in the subendothelial space. Whatever the mechanism after injury, our data indicate that a deficiency of p53 is associated with increased intima formation in response to cuff injury.…”

Adenovirus-Mediated Gene Transfer of Superoxide Dismutase and Catalase Decreases Restenosis after Balloon Angioplasty

“…Rabbit smooth muscle cells (SMCs) were isolated from the media of rabbit aorta (n = 6) by explant methods, as previously described [18]. SMCs were grown in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum.…”