Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

2004 ◽  
Vol 84 (3) ◽  
pp. 767-801 ◽  
Author(s):  
Gary K. Owens ◽  
Meena S. Kumar ◽  
Brian R. Wamhoff
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Injury ◽  
Molecular Mechanisms ◽  
Atherosclerotic Lesion ◽  
Cooperative Interaction ◽  
Marker Genes ◽  
Environmental Cues ◽  
Current State ◽  
Wide Range

The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

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

2007 ◽  
Vol 292 (1) ◽  
pp. C59-C69 ◽  
Author(s):  
Keiko Kawai-Kowase ◽  
Gary K. Owens
Keyword(s):  
Smooth Muscle ◽  
Molecular Mechanisms ◽  
Platelet Derived Growth Factor ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
Environmental Cues ◽  
Selective Marker ◽  
Current State ◽  
Active Repressor

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.

Abstract 332: Deletion of ADAMTS7 in Mice Reveals a Role in Vascular Smooth Muscle Cell Response to Injury

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Robert C Bauer ◽  
Georgios K Paschos ◽  
Christopher Yu ◽  
Michael S Parmacek ◽  
Daniel J Rader ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Molecular Mechanisms ◽  
Atherosclerotic Lesion ◽  
Vsmc Proliferation ◽  
Exon Trapping

The zinc metalloprotease ADAMTS7 was recently shown by GWAS to be a locus on chr15 for human coronary artery disease (CAD). However, the molecular mechanisms tying ADAMTS7 function to atherosclerosis are unknown. We hypothesized that ADAMTS7 may promote atherosclerosis by facilitating vascular smooth muscle cell (VSMC) proliferation and migration in vivo. We obtained mice containing an exon-trapping cassette between exon 4 and 5 of Adamts7, leading to premature termination of the mRNA and a grossly truncated protein. These mice bred normally and did not display any obvious phenotype. The exon trapping cassette also contained a LacZ reporter construct, allowing for XGal staining to determine gene expression. We assessed Adamts7 gene expression via XGal staining in multiple tissues of interest, including the heart, lungs, liver, and spleen. We also confirmed KO of the gene message through TaqMan rtPCR in additional tissues. We performed wire injury and sham surgeries of femoral arteries in adult Adamts7+/+ and -/- mice (N=4 and 5, respectively) and investigated lesion formation at 28 days. Adamts7 -/- mice showed reduced neointima formation (64%), intima-to-media ratio (47%) and percent stenosis (61%) as compared to wild type. By immunohistochemistry and Trichrome staining we observed trends toward reduced VSMC proliferation (Ki67), reduced collagen IV and fibronectin matrix staining, and less disruption of laminin in ADAMTS7 -/- injured arteries. Finally, ADAMTS7 immunofluorescence of human primary aortic SMCs revealed colocalization to cortactin domains at the leading edge of migrating SMCs as well as to cytoskeletal filaments. In summary, Adamts7 deletion attenuates the VSMC and matrix responses to arterial injury suggesting a role for ADAMTS7 in VSMC migration in atherosclerotic lesion initiation and progression.

The Role of Ubiquitin E3 Ligase in Atherosclerosis

2020 ◽  
Vol 28 (1) ◽  
pp. 152-168
Author(s):  
Zhi-Xiang Zhou ◽  
Zhong Ren ◽  
Bin-Jie Yan ◽  
Shun-Lin Qu ◽  
Zhi-Han Tang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Protein Modification ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Atherosclerotic Cardiovascular Disease ◽  
E3 Ligases

: Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

scholarly journals Apolipoprotein J/Clusterin Is Induced in Vascular Smooth Muscle Cells After Vascular Injury

Circulation ◽  
2001 ◽  
Vol 104 (12) ◽  
pp. 1407-1412 ◽  
Author(s):  
Masaaki Miyata ◽  
Sadatoshi Biro ◽  
Hiroshi Kaieda ◽  
Hideyuki Eto ◽  
Koji Orihara ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Injury ◽  
Muscle Cells ◽  
Apolipoprotein J

Exploring the molecular mechanisms of OSU-03012 on vascular smooth muscle cell proliferation

2010 ◽  
Vol 344 (1-2) ◽  
pp. 81-89 ◽  
Author(s):  
Wei-Wen Kuo ◽  
Jing-Ru Weng ◽  
Chih-Yang Huang ◽  
Chang-Hai Tsai ◽  
Wei-Hung Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Molecular Mechanisms ◽  
Smooth Muscle Cell Proliferation

Abstract 126: Differential Effects of Respectively Blocking Two BET Bromodomains on Vascular Smooth Muscle Cell Phenotype Transformation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Mengxue Zhang ◽  
Bowen Wang ◽  
Craig Kent ◽  
Lian-Wang Guo
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Molecular Mechanisms ◽  
Cell Phenotype ◽  
Dependent Manner ◽  
Stat3 Phosphorylation ◽  
Phenotype Transformation

Introduction: Intimal hyperplasia (IH) occurs primarily due to vascular smooth muscle cell (SMC) transformation from quiescent to pathogenic phenotypes (e.g. proliferation and inflammation). Identification and effective targeting of key epigenetic factors governing SMC pathogenic transformation may lead to novel therapeutic methods for prevention of IH. We previously found that globally blocking the bromo- and extra-terminal (BET) epigenetic “reader” family abrogated SMC phenotype transformation and IH. We further investigated the functions of the two BET bromodomains (Bromo1 and Bromo2). Hypothesis: Bromo1 and Bromo2 play different roles in SMC pathogenic transformation. Methods and Results: We pre-treated rat primary aortic SMCs (for 2h) with Olinone or RVX208, inhibitors specific for Bromo1 and Bromo2 respectively, and then stimulated SMC phenotype transformation. Whereas RVX208 abrogated PDGF-BB-stimulated SMC proliferation (BrdU assay) in a dose dependent manner, Olinone enhanced SMC proliferation at high concentrations (>20 μM). RVX208 at 50 μM reduced TNFα-induced SMC inflammation (MCP-1 ELISA) by 80%,but Olinone at the same concentration slightly increased MCP-1. Furthermore, whereas RVX208 abolished PDGF-BB or TNFα-induced STAT3 phosphorylation (Western blotting), Olinone slightly increased phospho-STAT3. Conclusions: Our results reveal that blocking two BET bromodomains respectively produces distinct effects on SMC phenotype transformation, suggesting their differential epigenetic functions. Further elucidation of the underlying molecular mechanisms should contribute to precise targeting of the BET family for optimal mitigation of IH.

Abstract 239: Olfactomedin 2 Regulates Vascular Smooth Muscle Cell Phenotypic Modulation by Mediating the Interaction Between Runx2 and SRF

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Ning Shi ◽  
Xiao-Bing Cui ◽  
Shi-You Chen
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Marker Genes ◽  
Important Process ◽  
Phenotypic Modulation ◽  
And Migration ◽  
Proliferation And Migration

Olfactomedin 2 (Olfm2) is a novel regulator for vascular smooth muscle cell (SMC) differentiation, but it is unclear whether Olfm2 is also involved in SMC phenotypic modulation, an important process associated with vascular injury. In this study, we found that Olfm2 was induced during PDGF-BB-induced SMC phenotypic modulation. Olfm2 knockdown attenuated PDGF-BB-induced suppression of SM marker genes including SM myosin heavy chain and SM22α, and also inhibited PDGF-BB-stimulated SMC proliferation and migration. On the other hand, Olfm2 overexpression down-regulated SM markers gene expression, and promoted SMC proliferation marker PCNA expression. Moreover, PDGF-BB slightly induced expression of Runx2, which interfered with the formation of SRF/myocardin ternary complex, but dramatically enhanced SRF-Runx2 interaction, suggesting that certain factors mediate SRF-Runx2 interaction. Indeed, Olfm2 physically interacted with both SRF and Runx2. Blockade of Olfm2 inhibited SRF association with Runx2, leading to increased association between SRF and myocardin, which in turn activated the transcription of SM markers, whereas overexpression of Olfm2 promoted SRF binding to Runx2. These results demonstrated that Olfm2 mediates the interaction between SRF and Runx2, contributing to SMC phenotypic modulation.

scholarly journals Krüppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids

2008 ◽  
Vol 295 (5) ◽  
pp. C1175-C1182 ◽  
Author(s):  
Tadashi Yoshida ◽  
Qiong Gan ◽  
Gary K. Owens
Keyword(s):  
Smooth Muscle ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
Physical Interaction ◽  
Oxidized Phospholipids ◽  
Differentiation Markers ◽  
Differentiation Marker

Phenotypic switching of vascular smooth muscle cells (SMCs), such as increased proliferation, enhanced migration, and downregulation of SMC differentiation marker genes, is known to play a key role in the development of atherosclerosis. However, the factors and mechanisms controlling this process are not fully understood. We recently showed that oxidized phospholipids, including 1-palmitoyl-2-(5-oxovaleroyl)- sn-glycero-3-phosphocholine (POVPC), which accumulate in atherosclerotic lesions, are potent repressors of expression of SMC differentiation marker genes in cultured SMCs as well as in rat carotid arteries in vivo. Here, we examined the molecular mechanisms whereby POVPC induces suppression of SMC differentiation marker genes in cultured SMCs. Results showed that POVPC induced phosphorylation of ERK1/2 and Elk-1. The MEK inhibitors U-0126 and PD-98059 attenuated POVPC-induced suppression of smooth muscle ( SM) α-actin and SM-myosin heavy chain. POVPC also induced expression of Krüppel-like factor 4 (Klf4). Chromatin immunoprecipitation assays revealed that POVPC caused simultaneous binding of Elk-1 and Klf4 to the promoter region of the SM α-actin gene. Moreover, coimmunoprecipitation assays showed a physical interaction between Elk-1 and Klf4. Results in Klf4-null SMCs showed that blockade of both Klf4 induction and Elk-1 phosphorylation completely abolished POVPC-induced suppression of SMC differentiation marker genes. POVPC-induced suppression of SMC differentiation marker genes was also accompanied by hypoacetylation of histone H4 at the SM α-actin promoter, which was mediated by the recruitment of histone deacetylases (HDACs), HDAC2 and HDAC5. Coimmunoprecipitation assays showed that Klf4 interacted with HDAC5. Results provide evidence that Klf4, Elk-1, and HDACs coordinately mediate POVPC-induced suppression of SMC differentiation marker genes.

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