Role of Mechanical Strain in Regulation of Differentiation of Vascular Smooth Muscle Cells
1996; Lippincott Williams & Wilkins; Volume: 79; Issue: 5 Linguagem: Inglês
10.1161/01.res.79.5.1054
ISSN1524-4571
Autores Tópico(s)Cardiomyopathy and Myosin Studies
ResumoHomeCirculation ResearchVol. 79, No. 5Role of Mechanical Strain in Regulation of Differentiation of Vascular Smooth Muscle Cells Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRole of Mechanical Strain in Regulation of Differentiation of Vascular Smooth Muscle Cells Gary K. Owens Gary K. OwensGary K. Owens Originally published1 Nov 1996https://doi.org/10.1161/01.RES.79.5.1054Circulation Research. 1996;79:1054–1055The differentiated vascular smooth muscle cell (SMC) is a highly specialized cell that expresses a unique repertoire of contractile proteins, ion channels, membrane receptors, and signaling molecules necessary for its contractile function (reviewed in Reference 1). The SMC, however, is not terminally differentiated and is capable of undergoing marked changes in phenotype in response to changes in local environmental cues that normally control its differentiation/maturation. For example, after vessel injury, fully differentiated medial SMCs undergo a process referred to as "phenotypic modulation," which is characterized by decreased expression of markers of differentiated SMCs, such as smooth muscle α-actin and smooth muscle myosin heavy chain (SM MHC), and by accelerated growth and increased synthesis of extracellular matrix components, which are important for repair of the damaged vessel.12 SMCs within atherosclerotic lesions also exhibit marked differences in morphology and protein expression patterns compared with normal medial SMCs.34 Importantly, phenotypic changes in intimal SMCs are clearly not simply a function of the growth state of the SMC, since alterations persist even when growth rates return to normal.5 Of particular significance, phenotypic alterations in intimal SMCs within atherosclerotic lesions include not only enhanced growth responsiveness but also altered lipid metabolism and increased matrix production, which are likely to play a major role in the development and/or progression of atherosclerosis. Despite the importance of changes in SMC phenotype in atherogenesis, surprisingly little is known regarding the mechanisms and factors that normally control the differentiation of the SMC and how these control processes are altered in vascular disease. The study in this issue of Circulation Research by Reusch et al6 is particularly significant in that it is one of the first studies, and in my opinion the most definitive study to date, identifying a positive differentiation influence/factor for vascular SMCs. Authors demonstrate that exposure of cultured rat aortic SMCs to mechanical stretch increased expression of the highly specific SMC differentiation marker SM MHC (both the SM-1 and SM-2 isoforms), whereas it decreased expression of the nonmuscle (NM) isoforms of myosin, NM-A and NM-B (or SMemb). The expression of SM-2 is particularly significant in that it is a very late marker of SMC differentiation/maturation and is one of the first markers that is downregulated when SMCs undergo phenotypic modulation both in vivo and in vitro.7 This demonstrates the retention of the "differentiation potential" of cultured SMCs and identifies mechanical forces as key factors or environmental cues in the control of the differentiation process in SMCs. Results are consistent with a previous study by Kanda and Matsuda8 demonstrating that exposure of cultured SMCs within a three-dimensional collagen type I matrix to periodic stretch induced alignment of cells parallel to the direction of stretch and increased the abundance of myofilaments and dense bodies, which are characteristic of differentiated SMCs. These results are also consistent with a large body of circumstantial evidence from studies in vivo suggesting an important role for mechanical influences in control of differentiation of SMCs1 in a manner similar to that in skeletal and cardiac muscle.9Paradoxically, Wilson et al1011 have previously demonstrated that mechanical stretch also induces enhanced growth of cultured SMCs via stimulation of autocrine production of platelet-derived growth factor (PDGF), which we have shown is a very potent and efficacious negative regulator of SMC differentiation.11213 Moreover, consistent with our observations, Reusch et al6 show that administration of PDGF-neutralizing antibodies dramatically enhanced induction of SM MHC isoforms by mechanical stretching. Thus, it appears that mechanical stretch is inducing opposing activities. The authors argue effectively that enhanced expression of SM MHC with mechanical stretching was not secondary to increased cell density, which is an important consideration, since we have previously demonstrated that expression of SM-1 and SM-2 is enhanced with increasing SMC density.14 Reusch et al suggest two alternative explanations for this paradox: (1) proliferation and altered myosin isoform expression are occurring in two distinct populations, or (2) cells are uniform, but a heterogeneous response could arise from the heterogeneous strain profile produced by the strain apparatus used. These are certainly viable possibilities that remain to be directly tested. However, it is also important to emphasize that it is now well established that growth and differentiation in SMCs are not mutually exclusive processes and that the effect of a given "growth factor" is not a direct function of its mitogenicity.115 Indeed, we have shown that PDGF-BB is unique among known SMC mitogens in its ability to coordinately downregulate the expression of multiple SMC differentiation marker proteins but that its effects are not directly coupled to its efficacy as a growth factor.11213 Consistent with these observations, during vascular development SMCs that are rapidly proliferating express many proteins characteristic of differentiated SMCs.16 Of interest, this is also a period during which hemodynamic stress/strain on the vessel wall is increasing. Thus, the two responses to mechanical strain observed by Ives and coworkers, as well as by others,17 may be appropriate for a vessel that is simultaneously undergoing rapid growth and differentiation/maturation. A key question will be to determine whether mechanical stretch stimulates similar responses in vascular SMCs in vivo and to determine what regulates the balance between growth versus differentiation signals in response to mechanical strain. The authors' observations that the response of SMCs varies depending on the matrix on which cells are plated (ie, no increase in SM myosin expression was seen in response to stretch when SMCs were grown on fibronectin, whereas stretch-induced growth responses were maximal on fibronectin) suggest that interaction of SMCs with specific extracellular matrix components may play a key role in determining the nature of the response to mechanical stimulation.A key unresolved issue is whether the effects of mechanical stretch observed by Ives and coworkers1011 are mediated at the transcriptional, posttranscriptional, and/or posttranslational levels. The authors' observations that stretch caused an increase in SM myosin protein and mRNA levels indicate that changes were not mediated solely at the translational and posttranslational levels. However, the differences in the kinetics of increases in SM-1 protein versus mRNA levels indicate that at least part of the effect was at the level of changes in protein stability. Note that there is considerable precedence for regulation of SMC differentiation at the posttranscriptional level in that effects of PDGF-BB in coordinately downregulating SM α-actin, SM MHC, and SM tropomyosin are mediated largely by selective destabilization of the transcripts encoding these SM contractile proteins without an effect on the nonmuscle variants of these proteins or a detectable change in transcription.1218 Thus, it is possible that the effects of stretch may not be at the level of gene transcription. However, there is also considerable precedence for stretch-responsive elements in the promoters of a number of contractile protein genes in skeletal and cardiac muscle,19 and this may also prove to be the case in SMCs.An additional important issue is to determine what mechanoreceptor mechanisms and signal transduction pathways are involved in mediating stretch effects in SMCs. This is an extremely active area of research in many cell types, and there are many possibilities, including stretch-activated ion channels and integrin-extracellular matrix–mediated signaling pathways (reviewed by Osol20 ).In summary, the study by Reusch et al6 represents an exciting and significant advance for the field of SMC biology and provides a strong foundation for further studies investigating mechanisms whereby mechanical factors influence SMC differentiation and hopefully will serve to stimulate much additional work on identification of other extrinsic factors that play a key role in control of the differentiated state of the SMC under both normal conditions and in vascular disease.FootnotesCorrespondence to Dr Gary K. Owens, Department of Molecular Physiology and Biological Physics, P.O. Box 10011, University of Virginia School of Medicine, Charlottesville, VA 22906-0011. References 1 Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev.1995; 75:487-517.CrossrefMedlineGoogle Scholar2 Schwartz SM, Campbell GR, Campbell JH. Replication of smooth muscle cells in vascular disease. Circ Res.1986; 58:427-444.CrossrefMedlineGoogle Scholar3 Kocher O, Gabbiani G. Cytoskeletal features of normal and atheromatous human arterial smooth muscle cells. Hum Pathol.1986; 17:875-880.CrossrefMedlineGoogle Scholar4 Glukhova MA, Kabakov AE, Frid MG, Ornatsky OI, Belkin AM, Mukhin DN, Orekhov AN, Koteliansky VE, Smirnov VN. Modulation of human aorta smooth muscle cell phenotype: a study of muscle-specific variants of vinculin, caldesmon, and actin expression. Proc Natl Acad Sci U S A.1988; 85:9542-9546.CrossrefMedlineGoogle Scholar5 Gordon D, Reidy MA, Benditt EP, Schwartz SM. Cell proliferation in human coronary arteries. Proc Natl Acad Sci U S A.1990; 87:4600-4604.CrossrefMedlineGoogle Scholar6 Reusch P, Wagdy H, Reusch R, Wilson E, Ives HE. Mechanical strain increases smooth muscle and decreases nonmuscle myosin expression in rat vascular smooth muscle cells. Circ Res..1996; 79:1046-1053.CrossrefMedlineGoogle Scholar7 Aikawa M, Sivam PN, Kuro-o M, Kimura K, Nakahara K, Takewaki S, Ueda M, Yamaguchi H, Yazaki Y, Periasamy M, Nagai R. Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis. Circ Res.1993; 73:1000-1012.CrossrefMedlineGoogle Scholar8 Kanda K, Matsuda T. Mechanical stress-induced orientation and ultrastructural change of smooth muscle cells cultured in three-dimensional collagen lattices. Cell Transplant.1994; 3:481-492.CrossrefMedlineGoogle Scholar9 Simpson DG, Carver W, Borg TK, Terracio L. Role of mechanical stimulation in the establishment and maintenance of muscle cell differentiation. Int Rev Cytol.1994; 150:69-94.CrossrefMedlineGoogle Scholar10 Wilson E, Sudhir K, Ives HE. Mechanical strain of rat vascular smooth muscle cells is sensed by specific extracellular matrix/integrin interactions. J Clin Invest.1995; 96:2364-2372.CrossrefMedlineGoogle Scholar11 Wilson E, Mai Q, Sudhir K, Weiss RH, Ives HE. Mechanical strain induces growth of vascular smooth muscle cells via autocrine action of PDGF. J Cell Biol.1993; 123:741-747.CrossrefMedlineGoogle Scholar12 Holycross BJ, Blank RS, Thompson MM, Peach MJ, Owens GK. Platelet-derived growth factor-BB–induced suppression of smooth muscle cell differentiation. Circ Res.1992; 71:1525-1532.CrossrefMedlineGoogle Scholar13 Blank RS, Owens GK. Platelet-derived growth factor regulates actin isoform expression and growth state in cultured rat aortic smooth muscle cells. J Cell Physiol.1990; 142:635-642.CrossrefMedlineGoogle Scholar14 Rovner AS, Murphy RA, Owens GK. Expression of smooth muscle and nonmuscle myosin heavy chains in cultured vascular smooth muscle cells. J Biol Chem.1986; 261:14740-14745.CrossrefMedlineGoogle Scholar15 Somasundaram C, Kallmeier RC, Babij P. Regulation of smooth muscle myosin heavy chain gene expression in cultured vascular smooth muscle cells by growth factors and contractile agonists. Basic Appl Mycol.1995; 6:31-36.Google Scholar16 Duband JL, Gimona M, Scatena M, Sartore S, Small JV. Calponin and SM 22 as differentiation markers of smooth muscle: spatiotemporal distribution during avian embryonic development. Differentiation.1993; 55:1-11.CrossrefMedlineGoogle Scholar17 Birukov KG, Shirinsky VP, Stepanova OV, Tkachuk VA, Hahn AW, Resink TJ, Smirnov VN. Stretch affects phenotype and proliferation of vascular smooth muscle cells. Mol Cell Biochem. 1996;131-139.Google Scholar18 Corjay MH, Blank RS, Owens GK. Platelet-derived growth factor-induced destabilization of smooth muscle α-actin mRNA. J Cell Physiol.1990; 145:391-397.CrossrefMedlineGoogle Scholar19 Sadoshima J, Jahn L, Takahashi T, Kulik TJ, Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells: an in vitro model of load-induced cardiac hypertrophy. J Biol Chem.1992; 267:10551-10560.CrossrefMedlineGoogle Scholar20 Osol G. Mechanotransduction by vascular smooth muscle. J Vasc Res..1995; 32:275-292.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Rahmani R, Baranoski J, Albuquerque F, Lawton M and Hashimoto T (2022) Intracranial aneurysm calcification – A narrative review, Experimental Neurology, 10.1016/j.expneurol.2022.114052, 353, (114052), Online publication date: 1-Jul-2022. Liu S and Lin Z (2021) Vascular Smooth Muscle Cells Mechanosensitive Regulators and Vascular Remodeling, Journal of Vascular Research, 10.1159/000519845, 59:2, (90-113), . 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