Common Signaling Elements in Response Pathways Activated by the Endothelial Survival Factors VEGF and Insulin

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dc.contributor.authorWang, Amanda Cyphersen
dc.contributor.committeechairHuckle, William R.en
dc.contributor.committeememberEyestone, Willard H.en
dc.contributor.committeememberWinkel, Brenda S. J.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2014-03-14T20:50:06Zen
dc.date.adate2008-12-30en
dc.date.available2014-03-14T20:50:06Zen
dc.date.issued2008-12-02en
dc.date.rdate2010-12-22en
dc.date.sdate2008-12-16en
dc.description.abstractDamage 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.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-12162008-161850en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-12162008-161850/en
dc.identifier.urihttp://hdl.handle.net/10919/36205en
dc.publisherVirginia Techen
dc.relation.haspartAmandaWang_Thesis_Final_ETD.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectCellular Signal Transductionen
dc.subjectReceptor Tyrosine Kinasesen
dc.subjectInsulinen
dc.subjectVascular Endothelial Growth Factoren
dc.titleCommon Signaling Elements in Response Pathways Activated by the Endothelial Survival Factors VEGF and Insulinen
dc.typeThesisen
thesis.degree.disciplineBiomedical Sciences and Pathobiologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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