Smooth muscle phenotypic modulation: Role in atherogenesis

Campbell, Gordon; Chamley-Campbell, J.

doi:10.1016/0306-9877(81)90084-0

Cited by 49 publications

(17 citation statements)

References 17 publications

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“…21 In atherosclerotic legion, VSMCs dedifferentiate into synthetic type in response to injury and/or growth factors and cytokines and migrate into atherosclerotic intima to contribute to the progression of atherosclerosis. [22][23][24] However, it remains unclear whether dedifferentiated VSMCs play a role in the formation of atherosclerotic intimal calcification. In the present study, we investigated the gene expressions of bone-calcification regulatory factors in redifferentiated and dedifferentiated VSMCs in vitro and found that paracrine osteogenic signals via BMP-2 were significantly enhanced when VSMCs became dedifferentiated.…”

Section: Conclusion-ourmentioning

confidence: 99%

Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo

Nakagawa

Ikeda

Akakabe

et al. 2010

ATVB

115

105

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Objective-Vascular calcification is an important risk factor for cardiovascular diseases. Here, we investigated a role of dedifferentiated vascular smooth muscle cells (VSMCs) in the atherosclerotic intimal calcification. Methods and Results-We prepared human cultured VSMCs in either redifferentiatiated or dedifferentiated state and analyzed the gene expressions of bone-calcification regulatory factors. Expression of bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblast differentiation, was significantly enhanced in dedifferentiated VSMCs. Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs. Conditioned medium from dedifferentiated VSMCs, but not from redifferentiated VSMCs, stimulated the osteoblastic differentiation of the mesenchymal progenitor C2C12 cells, which was abolished by BMP-2 knockdown. In atherosclerotic intima from apolipoprotein (apo)E-deficient mice, ␣SM-actin-positive cells, presumably dedifferentiated VSMCs, expressed BMP-2. We generated BMP-2-transgenic mice using ␣SM-actin promoter and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout).Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice. V ascular calcification has been an important risk factor for cardiovascular diseases as well as all-causal mortality. 1,2 There are several types of vascular calcification, such as calcification in intima associated with atherosclerosis and calcification in tunica media (medial calcification), which is often observed in elderly people and patients with diabetes mellitus and/or chronic kidney disease. 3 Recently, we have reported an important role of senescent vascular smooth muscle cells (VSMCs) in the formation of medial calcification associated with aging. 4 However, the molecular mechanism(s) governing atherosclerotic intimal calcification remains to be elucidated. Atherosclerotic calcification of coronary artery is a significant risk for the unsuccessful coronary intervention and balloon-induced coronary artery dissection. 5 Calcification score of coronary arteries assessed by electron beam computer tomography has been reported to correlate well with the incidence of cardiovascular diseases. 6 Furthermore, calcification was found to be a reliable marker of plaque instability, defined as plaques that have undergone rupture using autopsy specimens. 7 However, there is a controversy around this with arguments describing calcification as a marker of plaque stability as well. Negative correlation between extensive calcification and plaque instability was shown, and the pattern of calcification rather than the vo...

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Section: Conclusion-ourmentioning

confidence: 99%

Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo

Nakagawa

Ikeda

Akakabe

et al. 2010

ATVB

115

105

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“…Several authors have suggested that smooth muscle cells can be divided into two phenotypes: the contractile and the proliferating/synthetic smooth muscle cell type (Campbell and Chamley-Campbell, 1981;Campbell et al, 1989). Phenotype switches between these stages of differentiation have been suggested, but variation amongst smooth muscle cells derived from different organs and the lack of reliable differentiation markers have hampered investigations in this matter.…”

Section: Expression Of Smoothelinmentioning

confidence: 99%

“…The differentiation process is, contrary to that in striated muscle cells, reversible, a phenomenon referred to as modulation. As deduced from embryological studies, smooth muscle differentiation is characterized by the onset of expression of a particular set of proteins, some of which are characteristic for the different phenotypes (Campbell and Chamley-Campbell, 1981;Skalli et al, 1986;Campbell et al, 1989;Owens, 1995). For the understanding of smooth muscle differentiation, it is important to distinguish proteins that are characteristic for a given stage of smooth muscle differentiation.…”

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confidence: 99%

Smoothelin, a novel cytoskeletal protein specific for smooth muscle cells.

Loop

Schaart

Timmer

et al. 1996

The Journal of Cell Biology

223

183

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Abstract. The characterization of a novel 59-kD cytoskeletal protein is described. It is exclusively observed in smooth muscle cells by Northern blotting and immunohistochemical analysis and therefore designated "smoothelin." A human smooth muscle cDNA library was screened with the monoclonal antibody R4A, and a full-size cDNA of the protein was selected. The cDNA was sequenced and appeared to contain a 1,113-bp open reading frame. Based on the cDNA sequence, the calculated molecular weight of the polypeptide was 40 kD and it was demonstrated to contain two N-glycosylation sites. Computer assisted analysis at the protein level revealed a 56-amino acid domain with homologies of ~40% with a sequence bordering the actin-binding domains of dystrophin, utrophin, [3-spectrin and a-actinin. In situ hybridization demonstrated that human smoothelin is encoded by a single copy gene which is located on chromosome 22. Immunohistochemistry and Western blotting revealed synthesis of smoothelin in smooth muscle of species evolutionarily as far apart as human and teleost. Northern blotting indicated that sequence as well as size of the mRNA (~1,500 bases) are conserved among vertebrates. Cell fractionation studies and differential centrifugation showed that the protein cannot be extracted with Triton X-100, which indicates that it is a part of the cytoskeleton. Transfection of the human cDNA into smooth muscle cells and COS7 cells produced a protein of 59 kD, which assembled into a filamentous network. However, in rat heart-derived myoblasts association with stress fibers was most prominent. Smoothelin was not detected in primary or long term smooth muscle cell cultures. Also, transcription of smoothelin mRNA was almost instantly halted in smooth muscle tissue explants. We conclude that smoothelin is a new cytoskeletal protein that is only found in contractile smooth muscle cells and does not belong to one of the classes of structural proteins presently known.

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“…Inner elastic lamellae exist between the media and the intima. SMCs can exist in multiple phenotypic states, the extremes of which are termed as 'contractile' and 'synthetic' [7][8][9][10][11]. 'Contractile'-state SMCs contract in response to chemical and mechanical stimuli, and are responsible for maintaining vessel tone and regulating blood flow.…”

Section: Components Of Artery Wallmentioning

confidence: 99%