Mechanisms simultaneously regulate smooth muscle proliferation and differentiation

Abstract

Vascular smooth muscle cell (VSMC) differentiation and proliferation are two important physiological processes during vascular development. The phenotypic alteration from differentiated to proliferative VSMC contributes to the development of several major cardiovascular diseases including atherosclerosis, hypertension, restenosis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. Since the VSMC phenotype in these pathological conditions resembles that of developing VSMC during embryonic development, understanding of the molecular mechanisms that control VSMC differentiation will provide fundamental insights into the pathological processes of these cardiovascular diseases. Although VSMC differentiation is usually accompanied by an irreversible cell cycle exit, VSMC proliferation and differentiation occur concurrently during embryonic development. The molecular mechanisms simultaneously regulating these two processes, however, remain largely unknown. Our recent study demonstrates that cell division cycle 7, a key regulator of cell cycle, promotes both VSMC differentiation and proliferation through different mechanisms during the initial phase of VSMC differentiation. Conversely, Krüppel-like factor 4 appears to be a repressor for both VSMC differentiation and proliferation. This review attempts to highlight the novel role of cell division cycle 7 in TGF-β-induced VSMC differentiation and proliferation. The role of Krüppel-like factor 4 in suppressing these two processes will also be discussed.

Keywords: Krüppel-like factor 4; cell division cycle 7; differentiation; proliferation; vascular smooth muscle.

Fig. 1. Positive and negative regulation of cell differentiation and proliferation during vascular smooth muscle cell (VSMC) differentiation and phenotypic modulation.

A: Cdc7 stimulates VSMC differentiation and proliferation. Cdc7 interacts with Smad3 and enhances Smad3 binding to SBE in VSMC marker gene promoter, resulting in activation of SMC gene transcription and VSMC differentiation. Cdc7 binds to Dbf4, and Cdc7/Dbf4 phosphorylates MCM located on ORC, leading to initiation of DNA replication and VSMC proliferation. B: KLF4 inhibits VSMC differentiation and proliferation. KLF4 blocks SRF binding to CArG box, decreases myocardin expression, and recruits histone deacetylases to silence VSMC marker gene transcription and thus suppresses VSMC differentiation. KLF4 binds to p21WAF/Cip1 promoter and recruits p53 to induce p21WAF/Cip1 expression and thus inhibits VSMC proliferation.