Vascular Aging: from Smooth Muscle Cell Differentiation to Polyploidization
Abstract
Aging 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.
Description
Keywords
Biology--Cell, Biology--Molecular
Citation
Zhan, 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/28633