scholarly journals Molecular Mechanisms of the Exaggerated Growth of Vascular Smooth Muscle Cells in Hypertension

1997 ◽  
Vol 4 (2) ◽  
pp. 65-72 ◽  
Author(s):  
Noboru Fukuda
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Muscle Cells

scholarly journals 2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells

2015 ◽  
Vol 309 (12) ◽  
pp. E995-E1007 ◽  
Author(s):  
Lisa Rigassi ◽  
Federica Barchiesi Bozzolo ◽  
Eliana Lucchinetti ◽  
Michael Zaugg ◽  
Jürgen Fingerle ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Myosin Phosphatase ◽  
Downstream Signaling

2-Methoxyestradiol (2-ME), a metabolite of estradiol with little affinity for estrogen receptors, inhibits proliferation of vascular smooth muscle cells; however, the molecular mechanisms underlying this effect are incompletely understood. Our previous work shows that 2-ME inhibits initiation (blocks phosphorylation of ERK and Akt) and progression (reduces cyclin expression and increases expression of cyclin inhibitors) of the mitogenic pathway and interferes with mitosis (disrupts tubulin organization). Because the RhoA/ROCK1 pathway (RhoA → ROCK1 → myosin phosphatase targeting subunit → myosin light chain) is involved in cytokinesis, herein we tested the concept that 2-ME also blocks the RhoA/ROCK1 pathway. Because of the potential importance of 2-ME for preventing/treating vascular diseases, experiments were conducted in female human aortic vascular smooth muscle cells. Microarray transcriptional profiling suggested an effect of 2-ME on the RhoA/ROCK1 pathway. Indeed, 2-ME blocked mitogen-induced GTP-bound RhoABC expression and membrane-bound RhoA, suggesting interference with the activation of RhoA. 2-ME also reduced ROCK1 expression, suggesting reduced production of the primary downstream signaling kinase of the RhoA pathway. Moreover, 2-ME inhibited RhoA/ROCK1 pathway downstream signaling, including phosphorylated myosin phosphatase targeting subunit and myosin light chain; the ROCK1 inhibitor H-1152 mimicked these effects of 2-ME; both 2-ME and H-1152 blocked cytokinesis. 2-ME also reduced the expression of tissue factor, yet another downstream signaling component of the RhoA/ROCK1 pathway. We conclude that 2-ME inhibits the pathway RhoA → ROCK1 → myosin phosphatase targeting subunit → myosin light chain, and this likely contributes to the reduced cytokinesis in 2-ME treated HASMCs.

Serum deprivation results in redifferentiation of human umbilical vascular smooth muscle cells

2006 ◽  
Vol 291 (1) ◽  
pp. C50-C58 ◽  
Author(s):  
Mei Han ◽  
Jin-Kun Wen ◽  
Bin Zheng ◽  
Yunhui Cheng ◽  
Chunxiang Zhang
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Binding Activity ◽  
Serum Deprivation ◽  
Phenotypic Change ◽  
Phenotypic Reversion

Phenotypic change of vascular smooth muscle cells (VSMCs) from a differentiated to a dedifferentiated state accompanies the early stage of atherosclerosis and restenosis. Although much progress has been made in determining the molecular mechanisms involved in VSMC dedifferentiation, research on VSMC redifferentiation is hindered by the lack of an appropriate complete redifferentiation model. We established an in vitro model of redifferentiation by using postconfluent VSMCs from human umbilical artery. We demonstrated that serum-deprived VSMCs are capable of complete redifferentiation. After serum deprivation, postconfluent cultured human umbilical VSMCs became elongated and spindle shaped, with elevation of myofilament density, and reacquired contraction. Expressions of VSMC-specific contractile proteins, such as smooth muscle (SM) α-actin, SM-myosin heavy chain, calponin, and SM 22α, were increased and reached the levels in differentiated cells after serum deprivation. To determine the molecular mechanism of the phenotypic reversion, the levels of expression, phosphorylation, and binding activity of serum response factor (SRF), a key phenotypic modulator for VSMCs, were measured. The results showed that SRF binding activity with CArG motif was significantly increased after serum deprivation, whereas no changes were found in SRF expression and phosphorylation. The increased SRF binding activity was accompanied by an increase in expression of its coactivators such as myocardin. Furthermore, the phenotypic reversion was markedly inhibited by decoy double-strand oligodeoxynucleotides containing SM α-actin CArG motif, which was able to competitively bind to SRF. The results suggested that serum deprivation results in redifferentiation of human umbilical VSMCs. This novel model of VSMC phenotypic reversion should be valuable for research on vascular disease.

scholarly journals Runx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells

2007 ◽  
Vol 28 (3) ◽  
pp. 1147-1160 ◽  
Author(s):  
Toru Tanaka ◽  
Hiroko Sato ◽  
Hiroshi Doi ◽  
Carolina A. Yoshida ◽  
Takehisa Shimizu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Critical Role ◽  
Muscle Cells ◽  
Tightly Coupled

ABSTRACT Phenotypic plasticity and the switching of vascular smooth muscle cells (SMCs) play a critical role in atherosclerosis. Although Runx2, a key osteogenic transcription factor, is expressed in atherosclerotic plaques, the molecular mechanisms by which Runx2 regulates SMC differentiation remain unclear. Here we demonstrated that Runx2 repressed SMC differentiation induced by myocardin, which acts as a coactivator for serum response factor (SRF). Myocardin-mediated induction of SMC gene expression was enhanced in mouse embryonic fibroblasts derived from Runx2 null mice compared to wild-type mice. Forced expression of Runx2 decreased the expression of SMC genes and promoted osteogenic gene expression, whereas the reduction of Runx2 expression by small interfering RNA enhanced SMC differentiation in human aortic SMCs. Runx2 interacted with SRF and interfered with the formation of the SRF/myocardin ternary complex. Thus, this study provides the first evidence that Runx2 inhibits SRF-dependent transcription, as a corepressor independent of its DNA binding. We propose that Runx2 plays a pivotal role in osteogenic conversion tightly coupled with repression of the SMC phenotype in atherosclerotic lesions.

scholarly journals Activation of the GTPase ARF6 regulates Invasion of Human Vascular Smooth Muscle Cells by Stimulating MMP14 Activity

2021 ◽  
Author(s):  
Emilie Fiola-Masson ◽  
Julie Artigalas ◽  
Shirley Campbell ◽  
Audrey Claing
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Human Model ◽  
Ang Ii ◽  
Stimulation Of

Abstract Hormones and growth factors stimulate vascular smooth muscle cells (VSMC) invasive capacities during the progression of atherosclerosis. The GTPase ARF6 is an important regulator of migration and proliferation of various cell types, but whether this small G protein can be activated by a variety of stimuli to promote invasion of VSMC remains unknown. Here, we aimed to define whether Platelet-derived growth factor (PDGF), a mitogenic stimulant of vascular tissues, and Angiotensin II (Ang II), a potent vasoactive peptide, can result in the activation of ARF6 in a human model of aortic SMC (HASMC). We report that these two stimuli can promote loading of GTP on this ARF isoform. Knockdown of ARF6 reduced the ability of both PDGF and Ang II to promote invasion suggesting that this GTPase regulates key molecular mechanisms mediating degradation of the extracellular matrix and migration. We report that PDGF-BB-mediated stimulation of ARF6 results in the activation of the MAPK/ERK1/2, PI3K/AKT and PAK pathways essential for invasion of HASMC. However, Ang II-mediated stimulation of ARF6 only promotes activation of the MAPK/ERK1/2 and PAK pathways. These ARF6-mediated signaling cascades leads to activation of MMP14, which in turns controls the activity of MMP2 to degrade the extracellular matrix. Altogether, our findings demonstrate that the GTPase ARF6 acts as a molecular switch to regulate specific signaling pathways that coordinate the process of invasion.

scholarly journals Leptin augments recruitment of IRF-1 and CREB to thrombospondin-1 gene promoter in vascular smooth muscle cells in vitro

2016 ◽  
Vol 311 (2) ◽  
pp. C212-C224 ◽  
Author(s):  
Soumyadip Sahu ◽  
Rituparna Ganguly ◽  
Priya Raman
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Luciferase Reporter ◽  
Thrombospondin 1

We previously reported that high pathophysiological concentrations of leptin, the adipocyte-secreted peptide, upregulate the expression of a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in vascular smooth muscle cells. Moreover, this regulation was found to occur at the level of transcription; however, the underlying molecular mechanisms remain unknown. The goal of the present study was to investigate the specific transcriptional mechanisms that mediate upregulation of TSP-1 expression by leptin. Primary human aortic smooth muscle cell cultures were transiently transfected with different TSP-1 gene (THBS1) promoter-linked luciferase reporter constructs, and luciferase activity in response to leptin (100 ng/ml) was assessed. We identified a long THBS1 promoter (−1270/+750) fragment with specific leptin response elements that are required for increased TSP-1 transcription by leptin. Promoter analyses, protein/DNA array and gel shift assays demonstrated activation and association of transcription factors, interferon regulatory factor-1 (IRF-1) and cAMP response element-binding protein (CREB), to the distal fragment of the THBS1 promoter in response to leptin. Supershift, chromatin immunoprecipitation, and coimmunoprecipitation assays revealed formation of a single complex between IRF-1 and CREB in response to leptin; importantly, recruitment of this complex to the THBS1 promoter mediated leptin-induced TSP-1 transcription. Finally, binding sequence decoy oligomer and site-directed mutagenesis revealed that regulatory elements for both IRF-1 (−1019 to −1016) and CREB (−1198 to −1195), specific to the distal THBS1 promoter, were required for leptin-induced TSP-1 transcription. Taken together, these findings demonstrate that leptin promotes a cooperative association between IRF-1 and CREB on the THBS1 promoter driving TSP-1 transcription in vascular smooth muscle cells.

Abstract 383: STIM1 Deficiency in Vascular Smooth Muscle Cells Promotes Vascular Calcification in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Youfeng Yang ◽  
Yong Sun ◽  
Yabing Chen
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Calcification ◽  
Vascular Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Calcium Flux ◽  
Immunofluorescent Staining ◽  
Cellular Event

Vascular calcification is a characteristic feature of atherosclerosis. We and others have demonstrated that osteogenic differentiation of vascular smooth muscle cells (VSMC) contribute predominantly to the pathogenesis of vascular calcification in atherosclerosis. The key cellular event that leads to calcification is the secretion of matrix vesicles (MVs). However, the molecular regulation of MV release and the causal effect of MV release on VSMC calcification are poorly understood. The objective of this study is to investigate the function of a key calcium flux regulator, stromal interaction molecule 1 (STIM1), in regulating MV release and VSMC calcification; and to elucidate the underlying molecular mechanisms. SMC-specific STIM1-deficient mice (STIM1 Δ/Δ SMC ) were generated by breeding SM22α-Cre mice with STIM1 smooth muscle floxed mice (STIM1 f/f ). In vitro characterization using primary VSMC isolated from STIM1 Δ/Δ SMC and the control STIM1 f/f mice demonstrated that STIM1 deletion promoted VSMC calcification, although STIM1 deficiency has been linked to decreased calcium signals in smooth muscle cells. Increased release of MVs was demonstrated with the STIM1 Δ/Δ SMC VSMC compared with the control STIM1 f/f VSMC. Using the atherogenic ApoE -/- model, we demonstrated that SMC-specific STIM1 deficiency increased atherosclerotic vascular calcification in vivo. Consistently, increased MVs were determined in the serum of the STIM1 Δ/Δ SMC mice. Mechanistically, we found that STIM1 deficiency did not affect VSMC proliferation and survival, but decreased the expression of SMC-specific α-actin. The size of MVs released from STIM1 f/f and STIM1 Δ/Δ SMC VSMC appeared similar. However, MVs from the STIM1 Δ/Δ SMC VSMC contained a greater amount of calcium compared with those from the STIM1 f/f VSMC. Furthermore, immunofluorescent staining identified a rearrangement of actin-filament structure in the STIM1 Δ/Δ VSMC, a critical cellular event that controls the release of MVs. These studies have determined a new causative effect of VSMC-expressed STIM1 on atherosclerotic vascular calcification; and identified a novel link connecting STIM1 and actin-cytoskeleton rearrangement in regulating MV release and vascular calcification.

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