Micromanaging vascular smooth muscle cell differentiation and phenotypic modulation

Abstract

The phenotype of vascular smooth muscle cells (VSMCs) is dynamically regulated in response to various stimuli. In a cellular process known as phenotype switching, VSMCs alternate between a contractile and synthetic phenotype state. Deregulation of phenotype switching is associated with vascular disorders such as atherosclerosis, restenosis after angioplasty, and pulmonary hypertension. An important role for microRNAs (miRNAs) in VSMC development and phenotype switching has recently been uncovered. Individual miRNAs are involved in promoting both contractile and synthetic VSMC phenotype. In this review, we summarize recent advances in the understanding of miRNA function in the regulation of VSMC phenotype regulation.

Fig 1. Regulation of vSMC phenotype

A. In response to a variety of stimuli, vSMC switch between contractile phenotype and synthetic phenotype. Although not mutually exclusive, contractile phenotype is characterized by high expression of contractile genes and low rates of proliferation and migration. Conversely, synthetic vSMC express low levels of contractile genes and have increased rates of proliferation and migration. microRNAs reported to promote contractile and synthetic phenotype are indicated. B. Transcriptional regulation of vSMC contractile gene expression involves binding of SRF and either Myocardin or MRTF-A/B to CArG box elements located within the promoter of contractile genes. KLF4 is a potent repressor of Myocardin/MRTF-A/B activity.

Fig 2. Summary of miR-143/145 regulation

Diverse extracellular signals promote vSMC differentiation through regulation of miR-143/145 expression. Conversely, PDGF inhibits miR-143/145 expression both transcriptionally and post-transcriptionally at the Drosha processing step. Following transcription, pri-miR-145 is processed by Drosha and exported out of the nucleus by exportin-5. Dicer promotes the final cleavage step to generate mature miR-143 and miR-145 in the cytoplasm, which then promotes vSMC differentiation through the inhibition of pro-synthetic factors, such as KLF4.