Vascular smooth muscle cells differ from other smooth muscle cells: predominance of vimentin filaments and a specific alpha-type actin.

Gabbiani, Giulio; Schmid, Erika Nardon; Winter, Stefanie; Chaponnier, Christine; Ckhastonay, C. de; Vandekerckhove, Joël; Weber, Klaus; Franke, Werner W.

doi:10.1073/pnas.78.1.298

Cited by 421 publications

(205 citation statements)

References 42 publications

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“…PM, although bidirectional, in the present study refers to the process of transition from differentiated phenotype to dedifferentiated phenotype [1]. The differentiated SMC show a high level of expression of a unique repertoire of marker genes that includes smooth muscle α-actin (SMA) [2], smooth muscle myosin heavy chain (SMMHC) [3], calponin (CN) [4], SM-22α (SM22) [4,5], and h-caldesmon (CALD1) [6]. They also exhibit an extremely low rate of proliferation and synthetic activity.…”

Section: Introductionmentioning

confidence: 99%

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

Guo

Makarova

Cheng

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Lysophosphatidic acid (LPA) has been implicated as causative in phenotypic modulation (PM) of cultured vascular smooth muscle cells (VSMC) in their transition to the dedifferentiated phenotype. We evaluated the contribution of the three major LPA receptors, LPA 1 and LPA 2 GPCR and PPARγ, on PM of VSMC. Expression of differentiated VSMC-specific marker genes, including smooth muscle α-actin, smooth muscle myosin heavy chain, calponin, SM-22α, and hcaldesmon, was measured by quantitative real-time PCR in VSMC cultures and aortic rings kept in serum-free chemically defined medium or serum-or LPA-containing medium using wild-type C57BL/6, LPA 1 , LPA 2 , and LPA 1&2 receptor knockout mice. Within hours after cells were deprived of physiological cues, the expression of VSMC marker genes, regardless of genotype, rapidly decreased. This early PM was neither prevented by IGF-I, inhibitors of p38, ERK1/2, or PPARγ nor significantly accelerated by LPA or serum. To elucidate the mechanism of PM in vivo, carotid artery ligation with/without replacement of blood with Krebs solution was used to evaluate contributions of blood flow and pressure. Early PM in the common carotid was induced by depressurization regardless of the presence/absence of blood, but eliminating blood flow while maintaining blood pressure or after sham surgery elicited no early PM. The present results indicate that LPA, serum, dissociation of VSMC, IGF-I, p38, ERK1/2, LPA 1 , and LPA 2 are not causative factors of early PM of VSMC. Tensile stress generated by blood pressure may be the fundamental signal maintaining the fully differentiated phenotype of VSMC.

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Section: Introductionmentioning

confidence: 99%

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

Guo

Makarova

Cheng

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…SM α-actin is expressed in abundance in vascular smooth muscle, comprising 50-70% of total actin, with the remainder composed of β-cytoplasmic and γ-actins (9)(10)(11). Whereas SM α-actin expression is normally restricted to smooth muscle cells, it can also be expressed in nonmuscle cells, most notably myofibroblasts that use cell traction forces to remodel extracellular matrix (12).…”

mentioning

confidence: 99%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomeraseimmortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.thoracic aortic aneurysms | ACTA2 mutation | vascular disease | cell migration | human fibroblasts

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“…Consequently, it is not unexpected that the best studied SM-specific marker is smooth muscle ␣-actin, which first appears in the putative SMCs that envelope the dorsal aortae (9). Although it is transiently expressed during development in other mesodermally derived tissues (10) and in fibroblasts during wound repair (11), smooth muscle ␣-actin is normally expressed only in SMCs and SMC-like cells in the adult (12). A second well characterized SM-specific contractile protein is smooth muscle myosin heavy chain (SM-MHC).…”

mentioning

confidence: 99%

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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Vascular smooth muscle cells differ from other smooth muscle cells: predominance of vimentin filaments and a specific alpha-type actin.

Abstract: Different cell types contain distinct species of contractile and cytoskeletal proteins. This is especially evident in the class of the intermediate-sized (7-to 11-nm) filaments (refs.

Cited by 421 publications

References 42 publications

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

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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