Title page for ETD etd-12162008-161850


Type of Document Master's Thesis
Author Wang, Amanda Cyphers
URN etd-12162008-161850
Title COMMON SIGNALING ELEMENTS IN RESPONSE PATHWAYS ACTIVATED BY THE ENDOTHELIAL SURVIVAL FACTORS VEGF AND INSULIN.
Degree Master of Science
Department Biomedical Sciences and Pathobiology
Advisory Committee
Advisor Name Title
Huckle, William R. Committee Chair
Eyestone, Willard H. Committee Member
Winkel, Brenda S. J. Committee Member
Keywords
  • Cellular Signal Transduction
  • Receptor Tyrosine Kinases
  • Insulin
  • Vascular Endothelial Growth Factor
Date of Defense 2008-12-02
Availability unrestricted
Abstract
Damage to the vasculature is a common occurrence in diabetes mellitus. At the cellular level, dysfunction of vascular endothelial cells is often associated with diabetic conditions. Multiple agents maintain the endothelium, including vascular endothelial growth factor (VEGF), an endothelial cell mitogen/survival factor, and insulin, which has anti-apoptotic effects on endothelial cells in addition to regulating glucose homeostasis. Insulin and VEGF, upon activating their respective tyrosine kinase receptors, can engage the PI3-kinase/Akt, MAPK, and PLC-γ/PKC pathways. Thus, crosstalk between VEGF and insulin signaling may occur at numerous points. Our objectives were twofold: 1) to characterize the combined effects of insulin and VEGF on downstream elements, and 2) to determine the ability of signaling intermediates principally associated with either insulin or VEGF signaling to interact directly. After treatment with VEGF, insulin, or both, cells expressing both VEGF receptor-2 (KDR) and the insulin receptor were immunoprecipitated for total Akt and PLC-γ. Isolates from cells stimulated with both ligands demonstrated activation of PLC-γ and Akt that was less than additive over fifteen minutes. Conversely, cells pretreated with advanced glycation end products showed increased Akt phosphorylation. The effect of insulin on VEGF bioactivity was also measured by PLC-γ-mediated hydrolysis of phosphatidylinositol. These studies suggested suppressed VEGF activity in the presence of insulin. To examine direct signaling interactions, recombinant reagents capable of selective binding (via SH2 domains) to phosphorylated receptors were generated. Overall results showed relatively unaffected VEGF activity in the presence of insulin; however, this relationship is likely altered within the diabetic state.
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