Insulin-like growth factor effects on vascular smooth muscle cells are in part modulated via a G protein coupled pathway

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dc.contributor.supervisor Zahradka, Peter (Physiology) en
dc.contributor.author Perrault, Raissa
dc.date.accessioned 2010-09-23T17:50:30Z
dc.date.available 2010-09-23T17:50:30Z
dc.date.issued 2010-09-23T17:50:30Z
dc.identifier.uri http://hdl.handle.net/1993/4245
dc.description.abstract An important part of repair processes activated by vascular injury is the recruitment of vascular smooth muscle cells (SMC) from the existing contractile coat. Phenotypic modulation of SMCs enables these cells to proliferate and migrate into the vessel intima. Despite its importance in vessel repair, this plasticity of SMCs can also promote both the pathogenesis of atherosclerosis as well as neointimal formation following revascularization- induced injury. Vascular growth factors are major contributors to the migratory and proliferative responses to injury. IGF-1 is one such growth factor that elicits a response via its receptor, the IGF-1R, a classical tyrosine kinase receptor. However, it has been suggested that the IGF-1R may also be coupled to a heterotrimeric G protein and can thus initiate cellular responses via this alternate pathway. The objective of this study was to investigate the structural aspects of IGR-1R coupling to a heterotrimeric G protein in SMCs, as well as the contribution of this pathway to the cellular responses. In a porcine primary SMC culture model, IGF-1R co-precipitated with both the α- and β-subunits of a G protein, with the latter demonstrating activation dependent precipitation. The specific Gα class activated by IGF-1R was Gαi, in a manner that was independent of the activity of the tyrosine kinase. Both Gαi1 and Gαi2 directly interacted with the receptor. Gβγ mediated the activation of MAPK and its inhibition was sufficient to attenuate both the proliferation and migration of SMCs in vitro. In contrast, the contribution of Gαi was related to regulation of protein translation and histone modification. The data supports the conclusion that IGF-1 regulates the phenotype of vascular SMCs at least partially via a non-classical G protein-coupled receptor. Investigation into the individual subunits of the G protein complex led to the elucidation of a model in which both components play an integral role in the IGF-1 response, independent of the receptor tyrosine kinase activity. In one case, an interplay of specific Gαi-subunits leads to modulation of the VSMC translational and transcriptional responses, while in the other, release of the Gβγ-subunit activated the MAPK response in a manner that significantly contributes to both the migration and proliferation of SMCs. en
dc.format.extent 1468950 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject IGF-1R en
dc.subject G protein en
dc.subject Smooth muscle cells en
dc.subject Atherosclerosis en
dc.title Insulin-like growth factor effects on vascular smooth muscle cells are in part modulated via a G protein coupled pathway en
dc.type info:eu-repo/semantics/masterThesis
dc.degree.discipline Physiology en
dc.contributor.examiningcommittee Pierce, Grant (Physiology) Wigle, Jeffrey (Biochemistry & Medical Genetics) Halayko, Andrew (Physiology) en
dc.degree.level Master of Science (M.Sc.) en
dc.description.note October 2010 en

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