Cell Cycle–Dependent Regulation of Smooth Muscle Cell Activation

Abstract

Objective— Although numerous diseases involving cellular proliferation are also associated with phenotypic changes, there has been little direct evidence that cell phenotype and the cell’s response to external stimuli are modified during passage through different phases of the cell cycle. In this study, we demonstrate that an association exists between cell cycle progression and the expression of genes involved in cellular activation. Methods and Results— Early cell cycle arrest of aortic smooth muscle cells was found to inhibit the tumor necrosis factor α (TNFα)-induced upregulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, important markers of vascular cell activation in diseases such as atherosclerosis. A combination of immunocytochemistry and flow cytometry were used to document that TNFα-induced adhesion molecule upregulation was inhibited during G1-phase and S-phase, but not in G0-phase or G2/M-phase cells. The inhibition of adhesion molecule expression occurred at the level of transcription, as demonstrated by changes in the patterns of mRNA and protein accumulation in cycling and arrested cells. Conclusions— Early cell cycle phases may represent states in which the responses to a variety of stimuli that influence cell fate can be modulated, and these observations may have novel implications for the prevention and/or therapy of vascular proliferative, neoplastic, and inflammatory diseases.