title: Activation of Transcription Factor GAX and Concomitant Downregulation of IL-1β and ERK1/2 Modulate Vascular Smooth Muscle Cell Phenotype in 3D Fibrous Scaffolds.
abstract: Since vascular smooth muscle cells (VSMCs) display phenotypic plasticity in response to changing environmental cues, understanding the molecular mechanisms underlying the phenotypic modulation mediated by a three-dimensional (3D) scaffold is important to engineer functional vasculature. Following cell seeding into 3D scaffolds, the synthetic phenotype is desired to enable cells to expand rapidly and produce and assemble extracellular matrix components, but must revert to a quiescent contractile phenotype after tissue fabrication to impart the contractile properties found in native blood vessels. This study shows that 3D electrospun fibrous scaffolds regulate human coronary artery smooth muscle cells (HCASMCs) toward a more synthetic phenotype characterized by reduced contractile markers, such as smooth muscle alpha-actin and calponin. The reduction in contractile markers expression was mediated by endogenously expressed proinflammatory cytokine interleukin-1β (IL-1β). 3D topography transiently induces concomitant upregulation of IL-1β and MAPK ERK1/2 through nuclear factor-κB-dependent signaling pathway. An early burst of expression of IL-1β is essential for suppression of the homeobox transcription factor Gax and related cyclin-dependent kinase inhibitor p21(Cip1), which are key regulators for cells exiting from cell cycle. Our findings provide new insights for understanding signaling mechanisms of HCASMCs in electrospun 3D fibrous scaffolds, which have considerable value for application in vascular tissue engineering.
authors.affiliation: 1 Department of Chemical and Biochemical Engineering, Faculty of Engineering, The University of Western Ontario , London, Canada .
authors.forename: Shigang
authors.initials: S
authors.lastname: Lin
authors.affiliation: 1 Department of Chemical and Biochemical Engineering, Faculty of Engineering, The University of Western Ontario , London, Canada .|2 Graduate Program of Biomedical Engineering, The University of Western Ontario , London, Canada .
authors.forename: Kibret
authors.initials: K
authors.lastname: Mequanint
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D021621:Imaging, Three-Dimensional; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D054457:Tissue Scaffolds / Q000737:chemistry*; D014162:Transfection
chemical_list: D015415:Biomarkers; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; C484193:MEOX2 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000072000:NF-KappaB Inhibitor alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3