What controls smooth muscle phenotype?

Chamley-Campbell, J.; Campbell, Gordon

doi:10.1016/0021-9150(81)90145-3

Cited by 304 publications

(109 citation statements)

References 13 publications

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“…37 The process of dedifferentiation of vascular smooth muscle cells has been subject to intensive interest because of its importance in vascular pathology. It is clearly demonstrated that when vascular smooth muscle cells reenter the cell cycle, they undergo a transition from a contractile to a synthetic phenotype, 1 and this is associated with major changes in the Figure 6. Detection of SERCA2 (A), IP3R (B), and RyR (C) mRNA isoforms by RT-PCR in total aorta and RASMCs in culture.…”

Section: Discussionmentioning

confidence: 99%

“…Maturation of the rat aorta is associated with an increase in the level of SERCA2a mRNA, with the amounts of SERCA2b mRNA being identical in young and adult animals. 15 The goal of the present study was (1) to characterize the intracellular Ca 2ϩ pools in isolated RASMCs and to precisely identify the sarco(endo)plasmic reticulum Ca 2ϩ pumps and Ca 2ϩ channels in this cell type, (2) to study the changes in functional Ca 2ϩ pools and expression of genes encoding the sarco(endo)plasmic reticulum Ca 2ϩ pumps and Ca 2ϩ channels during RASMC proliferation in culture, and (3) to gain new insight into the mechanisms involved in the alteration of the phenotype of sarcoplasmic reticulum (SR) proteins during proliferation.…”

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confidence: 99%

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Intracellular Ca ²⁺ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Vallot

Combettes

Jourdon

et al. 2000

ATVB

100

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Abstract-Despite intensive interest in the dedifferentiation process of vascular smooth muscle cells, very little data are available on intracellular Ca 2ϩ signaling. The present study was designed to investigate the evolution of the intracellular Ca 2ϩ pools when rat aortic smooth muscle cells (RASMCs) proliferate and to define the mechanisms involved in the functional alterations. RASMCs were cultured in different conditions, and [Ca 2ϩ ] i was measured by use of fura 2. Expression of the sarco(endo)plasmic reticulum Ca 2ϩ pumps (SERCA2a and SERCA2b), Ca 2ϩ channels, the ryanodine receptor (RyR), and the inositol trisphosphate receptor (IP3R) was studied by reverse transcription-polymerase chain reaction and immunofluorescence. Antibodies specific for myosin heavy chain isoforms were used as indicators of the differentiation state of the cell, whereas an anti-proliferating cell nuclear antigen antibody was a marker of proliferation. SERCA2a, SERCA2b, RyR3, and IP3R-1 mainly were present in the aorta in situ and in freshly isolated RASMCs. These cells used the 2 types of Ca 2ϩ channels to release Ca 2ϩ from a common thapsigargin-sensitive store. Proliferation of RASMCs, induced by serum or by platelet-derived growth factor-BB, resulted in the disappearance of RyR and SERCA2a mRNAs and proteins and in the loss of the caffeine-and ryanodine-sensitive pool. The differentiated nonproliferative phenotype was maintained in low serum or in cells cultured at high density. In these conditions, RyR and SERCA2a were also present in RASMCs. Thus, expression of RyR and SERCA2a is repressed by cell proliferation, inducing loss of the corresponding Ca 2ϩ pool. In arterial smooth muscle, Ca 2ϩ release through RyRs is involved in vasodilation, and suppression of the ryanodine-sensitive pool might thus alter the control of vascular tone.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Intracellular Ca ²⁺ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Vallot

Combettes

Jourdon

et al. 2000

ATVB

100

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“…In contrast to skeletal and cardiac myocytes, VSMC do not terminally differentiate, and they undergo phenotypic modulation in vivo and in vitro in response to environmental signals (2,3). This process involves changes in gene expression, which convert these cells from a nonproliferative contractile phenotype to a proliferating synthetic one (2)(3)(4)(5). Indeed, a well defined characteristic of vascular occlusive disease, arterial interventions in response to disease, and in vitro subculturing of SMC is the phenotypic modulation of SMC from a normally quiescent, contractile state to one of increased growth, migration, and matrix synthesis.…”

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confidence: 99%

Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

Kaplan-Albuquerque

Bogaert

Putten

et al. 2005

Journal of Biological Chemistry

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In vascular smooth muscle cells (VSMC), platelet-derived growth factor (PDGF) suppresses expression of multiple smooth muscle contractile proteins, useful markers of differentiation. Conversely, hypertrophic agents induce expression of these genes. The goal of this study was to employ genomic approaches to identify classes of genes differentially regulated by PDGF and hypertrophic stimuli. Changes in gene expression were determined using Affymetrix RAE-230 GeneChips in rat aortic VSMC stimulated with PDGF. For comparison with a model hypertrophic stimulus, a microarray was performed with VSMC stably expressing constitutively active G␣ 16 , which strongly induces smooth muscle marker expression. We identified 75 genes whose expression was increased by exposure to PDGF and decreased by expression of G␣ 16 and 97 genes whose expression was decreased by PDGF and increased by G␣ 16 . These genes included many smooth muscle-specific proteins; several extracellular matrix, cytoskeletal, and chemotaxis-related proteins; cell signaling molecules; and transcription factors. Changes in gene expression for many of these were confirmed by PCR or immunoblotting. The contribution of signaling pathways activated by PDGF to the gene expression profile was examined in VSMC stably expressing gain-of-function H-Ras or myristoylated Akt. Among the genes that were confirmed to be differentially regulated were CCAAT/enhancer-binding protein ␦, versican, and nexilin. All of these genes also had altered expression in injured aortas, consistent with a role for PDGF in the response of injured VSMC. These data indicate that genes that are differentially regulated by PDGF and hypertrophic stimuli may represent families of genes and potentially be biomarkers for vascular injury.

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“…An additional feature of SMCs within atherosclerotic lesions is that cells exhibit marked differences in morphology and protein expression patterns as compared with normal medial SMCs (3-6), a process referred to as "phenotypic modulation" (7). This is characterized by decreased expression of proteins that are characteristic of differentiated SMCs, including the SM isoforms of contractile proteins, as well as altered growth regulatory properties, lipid metabolism, matrix production, and decreased contractility (reviewed in Ref.…”

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Expression of the Smooth Muscle Myosin Heavy Chain Gene Is Regulated by a Negative-acting GC-rich Element Located between Two Positive-acting Serum Response Factor-binding Elements

Madsen

Hershey

Hautmann

et al. 1997

Journal of Biological Chemistry

100

105

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To identify cis-and trans-acting factors that regulate smooth muscle-specific gene expression, we studied the smooth muscle myosin heavy chain gene, a rigorous marker of differentiated smooth muscle. A comparison of smooth muscle myosin heavy chain promoter sequences from multiple species revealed the presence of a highly conserved 227-base pair domain (nucleotides ؊1321 to ؊1095 in rat). Results of a deletion analysis of a 4.3-kilobase pair segment of the rat promoter (nucleotides ؊4220 to ؉88) demonstrated that this domain was necessary for maximal transcriptional activity in smooth muscle cells. Gel-shift analysis and site-directed mutagenesis demonstrated that one true CArG and another CArG-like element contained within this domain were both recognized by the serum response factor and were both required for the positive activity attributable to this domain. Additional studies demonstrated that mutation of a GC-rich sequence within the 227-base pair conserved domain resulted in a nearly 100% increase in transcriptional activity. Gel-shift analysis showed that this GC-rich repressor element was recognized by both Sp1 and Sp3. These data demonstrate that transcriptional control of the smooth muscle myosin heavy chain gene is highly complex, involving both negative and positive regulatory elements, including CArG sequences found in the promoters of multiple smooth muscle differentiation marker genes.Intimal migration and proliferation of vascular smooth muscle cells (SMCs) 1 are known to play an integral role in development of atherosclerotic disease (1, 2), and numerous factors have been identified that have growth promoting and/or chemotactic activity for SMCs (2). An additional feature of SMCs within atherosclerotic lesions is that cells exhibit marked differences in morphology and protein expression patterns as compared with normal medial SMCs (3-6), a process referred to as "phenotypic modulation" (7). This is characterized by decreased expression of proteins that are characteristic of differentiated SMCs, including the SM isoforms of contractile proteins, as well as altered growth regulatory properties, lipid metabolism, matrix production, and decreased contractility (reviewed in Ref. 8). Of particular significance, many of these phenotypic alterations in intimal SMCs cannot simply be viewed as a consequence of atherosclerotic disease, but rather are likely to play a major role in its development and/or progression.Although the SMC exhibits a high degree of plasticity and, unlike skeletal and cardiac myocytes, does not undergo terminal differentiation, it is a very specialized cell, whose differentiated function is dependent upon the coordinate regulation of a large number of cell type-specific/selective products, including contractile proteins, receptors, signal transduction molecules, and ion channels (8). Contractile proteins that are highly abundant and specific to the SMC represent obvious candidates for studying molecular control of SMC differentiation. Consequently, it is not unexpected that the bes...

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What controls smooth muscle phenotype?

Cited by 304 publications

References 13 publications

Intracellular Ca ²⁺ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Intracellular Ca ²⁺ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

Expression of the Smooth Muscle Myosin Heavy Chain Gene Is Regulated by a Negative-acting GC-rich Element Located between Two Positive-acting Serum Response Factor-binding Elements

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What controls smooth muscle phenotype?

Cited by 304 publications

References 13 publications

Intracellular Ca 2+ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Intracellular Ca 2+ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

Expression of the Smooth Muscle Myosin Heavy Chain Gene Is Regulated by a Negative-acting GC-rich Element Located between Two Positive-acting Serum Response Factor-binding Elements

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Intracellular Ca ²⁺ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation

Intracellular Ca ²⁺ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation