Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells

Abstract

Kawai-Kowase K, Owens GK. Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells. Am J Physiol Cell Physiol 292: C59 -C69, 2007. First published September 6, 2006; doi:10.1152/ajpcell.00394.2006.-Smooth muscle cell (SMC) differentiation is an essential component of vascular development and these cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. SMCs are not terminally differentiated and possess the ability to modulate their phenotype in response to changing local environmental cues. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMC with particular focus on examination of processes that contribute to the repression of SMC marker genes. We discuss the environmental cues which actively regulate SMC phenotypic switching, such as platelet-derived growth factor-BB, as well as several important regulatory mechanisms required for suppressing expression of SMC-specific/selective marker genes in vivo, including those dependent on conserved G/C-repressive elements, and/or highly conserved degenerate CArG elements found in the promoters of many of these marker genes. Finally, we present evidence indicating that SMC phenotypic switching involves multiple active repressor pathways, including Krüppel-like zinc finger type 4, HERP, and ERK-dependent phosphorylation of Elk-1 that act in a complementary fashion. serum response factor; platelet-derived growth factor-BB THERE IS CLEAR EVIDENCE that alterations in the differentiated state of the vascular smooth muscle cell (SMC) play a critical role in the pathogenesis of atherosclerosis, as well as a variety of other major human diseases, including hypertension, asthma, and vascular aneurysms. The precise nature of phenotypic switching is highly variable in these different diseases, with changes in atherosclerosis and vascular aneurysms involving rather profound changes in SMC morphology, function, and gene expression patterns, compared with the much more subtle changes in contractility associated with asthma and hypertension (69). Moreover, the nature and role of SMC phenotypic switching varies greatly at different stages of these diseases. This property is perhaps best illustrated by the pathogenesis of atherosclerosis where accelerated migration, proliferation, and production of extracellular matrix components by phenotypically modulated SMC play a critical role in lesion development. In contrast, the balance in production of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases, and extracellular matrix components by SMC (and macrophages) within the fibrous caps of advanced atheromatous lesions is a critical determinant of plaque stability (51). The fact that vascular SMC are not terminally differentiated and retain the ability to modulate their phenotype to changing environmental cues likely evolved as a key mechanism to allow repair of vascular injury and adaptation of SM...

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

“…Previous studies have demonstrated ERK1/2 is an important upstream regulator of VSMC phenotypic switch 20. Thus, we sought to determine if VPO1/HOCl promotes H 2 O 2 ‐induced VSMC phenotypic switch by activating ERK1/2.…”

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

“…The contractile phenotype of VSMCs is characterized by a low rate of cell proliferation and migration and high expression of contractile proteins such as α‐SMA, SM22 (transgelin), and smooth muscle myosin heavy chain 11 (MYH11) 24, 54, 55, 56, 57. The synthetic phenotype is characterized by a high rate of cell proliferation and migration and decreased expression of contractile proteins 24, 54, 55, 56, 57.…”

“…The contractile phenotype of VSMCs is characterized by a low rate of cell proliferation and migration and high expression of contractile proteins such as α‐SMA, SM22 (transgelin), and smooth muscle myosin heavy chain 11 (MYH11) 24, 54, 55, 56, 57. The synthetic phenotype is characterized by a high rate of cell proliferation and migration and decreased expression of contractile proteins 24, 54, 55, 56, 57. Disruption of the balance of the VSMCs phenotypes (for example, a transition from a contractile phenotype to a synthetic phenotype) will favor VSMCs proliferation and migration, leading to development of neointimal formation and restenosis after vascular injury 24, 55, 56, 57, 58.…”

“…The SRF is a key transcription factor for phenotypic switching of VSMCs by binding to the promoter/regulatory regions of VSMCs‐specific contractile genes, specifically to the cis‐acting DNA sequence CArG box (CC[A/T]6GG), to induce their expression 55, 56, 57, 58. Western blots and real‐time PCR analyses showed that although AGGF1 protein treatment can reverse downregulation of contractile genes/proteins α‐SMA, SM22, and MYH11 by PDGF‐BB in VSMCs, but the effects were completely lost in cells with knockdown of SRF expression by small interfering RNA (+siSRF) (Figure 6G and 6H).…”

Tollip Negatively Regulates Vascular Smooth Muscle Cell–Mediated Neointima Formation by Suppressing Akt‐Dependent Signaling

“…During surgical revascularization, the integrity of the endothelium may be damaged by mechanical injuries and result in the infiltration of inflammatory cells. Both dysfunctional endothelial cells and inflammatory cells synthesize and secrete various cytokines and growth factors, especially platelet‐derived growth factor (PDGF), which facilitates the switch of VSMCs from a contractile phenotype to a synthetic phenotype 5. Subsequently, the synthetic VSMCs, which express decreased levels of adult smooth muscle–specific proteins, migrate from the media into the intimal layer and proliferate to form neointimal lesions 6.…”