Origin and differentiation of vascular smooth muscle cells

Abstract

Vascular smooth muscle cells (SMCs), a major structural component of the vessel wall, not only play a key role in maintaining vascular structure but also perform various functions. During embryogenesis, SMC recruitment from their progenitors is an important step in the formation of the embryonic vascular system. SMCs in the arterial wall are mostly quiescent but can display a contractile phenotype in adults. Under pathophysiological conditions, i.e. vascular remodelling after endothelial dysfunction or damage, contractile SMCs found in the media switch to a secretory type, which will facilitate their ability to migrate to the intima and proliferate to contribute to neointimal lesions. However, recent evidence suggests that the mobilization and recruitment of abundant stem/progenitor cells present in the vessel wall are largely responsible for SMC accumulation in the intima during vascular remodelling such as neointimal hyperplasia and arteriosclerosis. Therefore, understanding the regulatory mechanisms that control SMC differentiation from vascular progenitors is essential for exploring therapeutic targets for potential clinical applications. In this article, we review the origin and differentiation of SMCs from stem/progenitor cells during cardiovascular development and in the adult, highlighting the environmental cues and signalling pathways that control phenotypic modulation within the vasculature.

Figure 1

Developmental fate map for SMCs The different colours represent the different embryonic origins for SMCs as indicated in the key.

Figure 2

An overview of the involvement of TGF-β, Wnt and integrin signalling in the differentiation of stem cells towards the smooth muscle lineage In TGF-β signalling, the binding of a TGF-β ligand to the TGF-β receptor catalyses the phosphorylation of the Smad2/3 molecule prior to its translocation to the nucleus. The Smads can then bind to a Smad binding element with various transcription factors. In canonical Wnt signalling, the Wnt ligand, Frizzled receptor protein and LRP form complexes to activate a cytosolic protein called Dishevelled. Activated Dishevelled inhibits the β-catenin destruction complex and thus increases the stabilization of β-catenin by escaping destruction via proteasomes and then accumulates in the cytosol and nucleus. In the nucleus, β-catenin forms a complex with T-cell factor (TCF) proteins. The complex activates the transcription of specific target genes, which drives mesoderm and SMC gene expression. This promotes the recruitment and the binding of the SRF–myocardin complex to the CArG elements found in the promoter region of most SMC-specific gene. Meanwhile, integrins bind to collagen that initiates signalling for cytoskeleton rearrangement, which is essential for SMC differentiation. SBE: Smad binding element; SRF: serum response factor; TF: transcription factor.

Figure 3

miRNA mediated stem cell differentiation into SMCs miR-145 and miR-143 enhance the binding of myocardin and SRF to the CArG box, which in turn positively regulates their expression. Myocardin expression is also enhanced by miR-221 via the inhibition of c-kit expression. miR-145 and miR-143 expression, along with mIR-1 also inhibit myocardin repressors such as KLF4 and ELK-1. This promotes the expression of SMC differentiation markers such as SMαA, SM22α and SMMHC.

Figure 4

Proposed model for the role of Cbx3 in SMC differentiation During the early phases of stem cell differentiation, histone modifications such as H3K9 occur within the promoter region of SMC differentiation genes. These regions can be recognized specifically by Cbx3 through the CD domain. After binding, Cbx3 functions as a bridge/anchor protein to recruit the SMC specific transcription factor SRF to the chromosome through interaction with Dia-1. This in turn facilitates SRF binding to the CArG elements within the promoter–enhancer region of SMC-specific genes, thereby regulating SMC differentiation from stem cells. (Adapted from Supplemental Figure VI of Xiao et al. (2011).)