Date on Master's Thesis/Doctoral Dissertation
12-2012
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Biochemistry and Molecular Biology
Committee Chair
Bhatnagar, Aruni
Author's Keywords
Cardiovascular; vascular smooth muscle; phenotype; PDGF autophagy; O-GlcNAc
Subject
Vascular smooth muscle--Physiology
Abstract
Vascular injury and chronic arterial diseases such as atherosclerosis and restenosis result in exposure of vascular smooth muscle cells (VSMCs) to increased concentrations of growth factors triggering a change from a contractile to a synthetic phenotype. The mechanisms by which growth factors trigger VSMC phenotype transitions remain unclear. Because phenotype switching involves the removal of contractile proteins, we hypothesized that autophagy is an essential modulator of VSMC phenotype. Also, the conversion to the synthetic phenotype is accompanied by cellular changes that trigger metabolic changes to meet the increasing demands for cellular energy. Little is known however about the contributions of different substrates metabolized for energy production and how these metabolic changes integrate with phenotype switching and VSMC proliferation. We further hypothesize that metabolic changes induced by PDGF are required for phenotype switching and proliferation. Studies presented here show that: 1) Treatment of VSMCs with platelet-derived growth factor PDGF-BB results in activation of autophagy which is required for degradation of contractile proteins during phenotype switching; 2) Increased glycolytic flux caused by PDGF treatment is required for expression of the synthetic cytokine osteopontin and for proliferation; and 3) Mitochondria fragmentation and increased fatty acid oxidation are required for PDGF-induced VSMC proliferation. These results support the overall hypothesis that autophagy and changes in intermediary metabolic pathways are modulators of PDGF-induced phenotype transition. Our findings suggest that autophagy-directed therapies may provide effective treatments against vascular diseases such as atherosclerosis and restenosis.
Recommended Citation
Salabei, Joshua Kuimeta, "Regulation of vascular smooth muscle cell phenotype." (2012). Electronic Theses and Dissertations. Paper 1250.
https://doi.org/10.18297/etd/1250