title: Disruption of actin cytoskeleton mediates loss of tensile stress induced early phenotypic modulation of vascular smooth muscle cells in organ culture.
abstract: Aorta organ culture has been widely used as an ex vivo model for studying vessel pathophysiology. Recent studies show that the vascular smooth muscle cells (VSMCs) in organ culture undergo drastic dedifferentiation within the first few hours (termed early phenotypic modulation). Loss of tensile stress to which aorta is subject in vivo is the cause of this early phenotypic modulation. However, no underlying molecular mechanism has been discovered thus far. The purpose of the present study is to identify intracellular signals involved in the early phenotypic modulation of VSMC in organ culture. We find that the drastic VSMC dedifferentiation is accompanied by accelerated actin cytoskeleton dynamics and downregulation of SRF and myocardin. Among the variety of signal pathways examined, increasing actin polymerization by jasplakinolide is the only one hindering VSMC dedifferentiation in organ culture. Moreover, jasplakinolide reverses actin dynamics during organ culture. Latrunculin B (disrupting actin cytoskeleton) and jasplakinolide respectively suppressed and enhanced the expression of VSMC markers, SRF, myocardin, and CArG-box-mediated SMC promoters in PAC1, a VSMC line. These results identify actin cytoskeleton degradation as a major intracellular signal for loss of tensile stress-induced early phenotypic modulation of VSMC in organ culture. This study suggests that disrupting actin cytoskeleton integrity may contribute to the pathogenesis of vascular diseases.
authors.affiliation: Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Jian-Pu
authors.initials: JP
authors.lastname: Zheng
authors.forename: Donghong
authors.initials: D
authors.lastname: Ju
authors.forename: Jianbin
authors.initials: J
authors.lastname: Shen
authors.forename: Maozhou
authors.initials: M
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000199:Actins / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000235:genetics*; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology*; D047630:Depsipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010641:Phenotype; D013314:Stress, Mechanical; D053778:Thiazolidines / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D050808:ets-Domain Protein Elk-4 / Q000235:genetics / Q000378:metabolism; D000099251:Myocardin
chemical_list: D000199:Actins; D015415:Biomarkers; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D009687:Nuclear Proteins; D053778:Thiazolidines; D015534:Trans-Activators; D050808:ets-Domain Protein Elk-4; D000099251:Myocardin; C494194:Elk4 protein, mouse; C057531:jasplakinolide; C037068:latrunculin B