Regulation of vascular smooth muscle cell signaling and metabolism by platelet-derived growth factor.

摘要

Growth factors are important inducers of vascular cell growth whose regulation is altered during the pathogenesis of atherosclerosis. An increase in growth factor and cytokine production, as well as lipid oxidation is observed in cardiovascular disease (CVD) and contributes to altered vascular cell signaling, exacerbated atherosclerotic lesions and heart failure. A change in cellular bioenergetic status due to mitochondrial dysfunction or damage has also been noted in CVD. In this thesis, we first examine cell signaling pathways in vascular smooth muscle cells (VSMC) which are activated in response to platelet-derived growth factor (PDGF) and regulate the cell cycle protein changes associated with proliferation. Next, we investigate the role of the phosphoinositide-3-kinase in the regulation of glycolysis and examine how glucose utilization and substrate availability for mitochondrial respiration can modulate the proliferative response of VSMC to PDGF. Through this study we highlight a novel link between the regulation of cellular glycolysis products and mitochondrial function. Finally, we examine the regulation of protein O-linked glycosylation in the regulation of mitochondrial bioenergetics and its implications on VSMC proliferation. This study highlights the importance of mitochondrial respiratory function in the observed PDGF-dependent effects. Together, these studies suggest a role for the metabolic changes that alter mitochondrial bioenergetics in the responses of vascular cells to growth stimuli and open avenues for further study for potential therapeutic agents.