Vascular Aging: from Smooth Muscle Cell Differentiation to Polyploidization

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atmire.migration.oldid4654
dc.contributor.advisorZheng, Xi-Long
dc.contributor.authorZhan, Shi
dc.contributor.committeememberXilong, Zheng
dc.contributor.committeememberCarlos, Fernandes-Patron
dc.contributor.committeememberBonni, Shirin
dc.contributor.committeememberWalsh, Michael
dc.contributor.committeememberRiabowol, Karl
dc.date.accessioned2016-07-14T18:09:04Z
dc.date.available2016-07-14T18:09:04Z
dc.date.issued2016
dc.date.submitted2016en
dc.description.abstractAging is associated with various changes in the vascular system at different structural and functional levels. These changes include increased arterial wall thickness, luminal dilation and reduced compliance. As a major component of the vascular wall, vascular smooth muscle cells (VSMCs) play an important role in exhibiting proper vascular functions. VSMCs behaviors are significantly modified by vascular aging. In this thesis, we study VSMC phenotypic modulation and polyploidiation in vascular aging through three projects. (1) Vascular aging switches VSMC phenotype from a differentiated to a dedifferentiated phenotype, which is characteristic in atherosclerosis. As an important transcription co-activator, myocardin regulates the expression of SM-differentitation marker genes and acts as a critical regulator in VSMC phenotypic modulation in response to various factors. In this thesis, we showed that GSK-3β positively regulates the expression of SM-differentiation markers in VSMCs. We also found that GSK-3β phosphorylats and enhances myocardin transcriptional activity through increasing the recruitment of myocardin to the promoter of its target gene and positively regulates myocardin gene expression. In conclusion, these results suggest that GSK-3β promotes VSMC differentiation through the regulation of myocardin activity. (2) VSMCs polyploidization is a biomarker of vascular aging. VSMC polyploidization and apoptosis co-exist in the aged or hypertensive vascular wall, but whether polyploidization contributes to VSMC apoptosis remains unknown. In this thesis, we found that nocodazole (ND), a microtubule-interfering reagent, induces VSMC polyploidization and apoptosis in a temporal order. Inhibition of ND-induced VSMC polyploidization abolished further apoptosis, suggesting a causal relatioinship between VSMC polyploidization and apoptosis. Also, we identified that mTOR signaling is involved in ND-induced VSMC polyploidization. (3) Accumulative studies have pointed a potential role of mTOR signaling in aging. To further establish the role of mTOR in VSMCs polyploidiation in aging, we established a T-REx system to overexpress mTOR in VSMCs. Overexpression of mTOR activated mTORC1 signaling and further induced VSMC polyploidization and senescence. We also found that autophagy which is negatively regulated by mTORC1 signaling is not involved in mTOR-induced VSMC polyploidy, although autohphagy has been well-established in VSMC senescence. We conclude that mTORC1 signaling induces VSMC polyploidization and senescence through different downstream effecters.en_US
dc.identifier.citationZhan, S. (2016). Vascular Aging: from Smooth Muscle Cell Differentiation to Polyploidization (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28633en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/28633
dc.identifier.urihttp://hdl.handle.net/11023/3138
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectBiology--Molecular
dc.subject.classificationSmooth muscle cellen_US
dc.subject.classificationDifferentiationen_US
dc.subject.classificationpolyploidizationen_US
dc.subject.classificationmTORen_US
dc.titleVascular Aging: from Smooth Muscle Cell Differentiation to Polyploidization
dc.typedoctoral thesis
thesis.degree.disciplineCardiovascular & Respiratory Sciences
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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