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. VSMCs not only enter cell cycle and proliferate, thereby contributing to neointima formation, but also become "activated," a term referring to the expression of cytokines, adhesion molecules, chemoattractants, proteolytic enzymes, and other molecules not normally expressed in the quiescent, contractile VSMCs of the medial layer of the vessel wall. For example, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) have been documented on neointimal VSMCs of animal models of atherosclerosis, restenosis, and transplant vasculopathy, as well as in human plaques. 3-7 These molecules, in turn, likely mediate and facilitate a robust inflammatory response and the further proliferation and migration of VSMCs. 1,8 Because both activated VSMCs and proliferating VSMCs were detected within the same neointimal lesion, it was generally assumed that proliferating cells are activated cells. However, this supposition has never been proven. Furthermore, it is not known whether activation and proliferation of See page 804 cells during atherogenesis are parallel-occurring but independent phenomena, or whether the activation state of a cell is influenced by its entry into and its progression through the different phases of the cell cycle. In a series of recent studies, our laboratory and others have found that vascular cell cycle arrest not only inhibits cellular proliferation and, as a result, neointima formation, but also ameliorates changes in vascular cell phenotype and actually reduces the heightened susceptibility of certain vessels to atherosclerosis or vasculopathy. 9,10 The current study, therefore, tested the hypothesis that an association exists between cell cycle progression and the susceptibility of vascular cells to cytokine induced adhesion molecule expression on the cell surface. We were able to demonstrate that VCAM-1 and ICAM-1 expression were inhibited during the G1-phase and S-phase of cell cycle. Methods and Results-Early

Gambogic Acid Induces G0/G1 Cell Cycle Arrest and Cell Migration Inhibition Via Suppressing PDGF Receptor β Tyrosine Phosphorylation and Rac1 Activity in Rat Aortic Smooth Muscle Cells

“…Cell cycle regulatory molecules, such as CDKs and cyclins, are related to the G1 phase of the cell cycle [35][36][37] . In the present study we found that VSMC cell cycle arrest in G0/G1 phase was induced by GA pretreatment; therefore, the effects of GA on expressions of CDK2, CDK4, cyclin E and D1 were further examined.…”

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

“…Modulation of the expression and function of cell cycle regulatory proteins (including CDKs, cyclins, CKIs, p53, and pRb) provides an important mechanism for growth inhibition (9,10,49,50). The fact that genistein permitted RASMC arrest in G 0 /G 1 phase suggests that modulations of several cell cycle regulatory proteins may occur after genistein treatment.…”

“…Generally, the cell cycle is regulated by the coordinated action of cyclin-dependent kinases (CDK) in association with their specific regulatory cyclin proteins. Thus, functional activation of CDK-cyclin is required for cell cycle progression (8,9). The kinase activity of these CDK-cyclin complexes is inhibited by two classes of cyclin-dependent kinase inhibitors (CKIs) (10).…”

Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

“…Under physiologic conditions, however, the endothelium is not static (3). Pulmonary artery cells are subjected to mechanical forces in the form of cyclic stretch and shear stress resulting from blood pressure and blood flow (4).…”