Smooth Muscle Cell Differentiation: Model Systems, Regulatory Mechanisms, and Vascular Diseases

Abstract

Smooth muscle cell (SMC) differentiation is an important process during vascular development. The highly differentiated mature SMCs play critical roles in maintaining structural and functional integrity of blood vessels. However, SMCs are not terminally differentiated, and their phenotype can be modulated between contractile and proliferative states in response to various environmental conditions. Alterations in SMC phenotype contribute to a number of major cardiovascular diseases such as atherosclerosis, hypertension and restenosis following angioplasty, etc. The goal of this review is to provide a brief overview of the recent advancements in our understanding of SMC differentiation and the development of in vitro SMC differentiation models, with a particular emphasis on examination of molecular mechanisms involved in the regulation of SMC differentiation and phenotypic modulation. J. Cell. Physiol. 231: 777-787, 2016. © 2015 Wiley Periodicals, Inc.

Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells

“…L + culture conditions also upregulated the expression of 54 transcriptional or translational proteins, while biomarker analysis found significant differences for 15 proteins that are markers for vSMC identity, including tenascin-C and versican, which are associated with the synthetic phenotype. Furthermore, pathway analysis suggested that lactate altered the activity of mechanisms that regulate cell proliferation, survival, and migration; protein synthesis; gene transcription; and differentiation (Table 1) 4 ; and the changes associated with lactate and hypoxia tended to not differ significantly (e.g., both conditions increased ILK signaling, which has been linked to the synthetic vSMC phenotype). Follow-up assessments via Western blot (Figure 6A) and quantitative RT-PCR (Figure 6B) confirmed that both lactate and hypoxia upregulate the expression of Yes-associated protein (Yap), which participates in the Hippo signaling pathway, as well as mechanistic target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK), which are components of pathways involved in fibrosis and/or injury repair.…”

“…1 The diversity of vSMC function is reflected in their phenotypes, which compose a spectrum that ranges from predominantly contractile cells at one end to predominantly synthetic cells at the other. The contractile and synthetic phenotypes are characterized by substantial differences in marker expression, morphology, and activity, 2, 3 and some evidence suggests that contractile cells can adopt a more synthetic phenotype in response to ischemic injury, 4 but the mechanisms that activate this phenotypic switch are poorly understood.…”

A New Editor of Smooth Muscle Phenotype

“…This unusual ability to de-differentiate is especially important since SMC phenotypic modulation contributes to multiple cardiovascular pathologies, including atherosclerosis and restenosis post-angioplasty. In response to growth factors released at sites of injury, such as platelet-derived growth factor (PDGF), mature SMC can re-enter the cell cycle, become migratory, and de-differentiate to a synthetic phenotype capable of extensive extracellular matrix deposition for vascular repair (1). Much of the research on SMC phenotypic switching has focused on transcriptional regulation of the contractile (differentiated) versus synthetic (de-differentiated) phenotype.…”

“…These include SM α-actin ( ACTA2 ) and SM-myosin heavy chain ( MYH11 ). These proteins are downregulated during SMC de-differentiation, which makes them a tangible biochemical readout of cellular differentiation status (1). A substantial body of work has demonstrated that contractile protein induction occurs largely at the level of transcriptional control, mediated by core factors including the CArG element binding protein serum response factor (SRF) and co-factor myocardin (3).…”

Differentiation and Application of Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells

“…22 As such, researchers seeking to delineate key signaling pathways required for the differentiation of stem cells into VSMCs use these as end points to determine whether a successful VSMC phenotype has been reached. This section does not cover all recognized signaling pathways regulating VSMC differentiation (eg, serum response factor [SRF]/myocardin complex, TGF-β, and platelet-derived growth factor-BB [PDGF-BB], Notch, retinoic acid, reactive oxygen species, small GTPase RhoA, and extracellular matrix-integrin signaling, as well as micro-RNAs), which has been extensively discussed in other reviews, [23][24][25] but instead summarizes the recent progress in this area ( Figure 2). …”