This study aimed to characterize the roles of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR) and ErbB2, and their downstream signalling pathways in diabetes-induced vascular dysfunction. Studies in the mesenteric vascular bed of streptozotocin (STZ)-induced diabetic rats showed that exaggerated vasoconstrictor response to noradrenaline and endothelin-1, and attenuated vasodilator response to carbachol in STZ-diabetic rats was normalized by treatment with either genistein (general RTK inhibitor) or with AG1478 (selective EGFR inhibitor). Higher levels of phosphorylated (p)EGFR and pErbB2 were seen in mesenteric tissues from diabetic rats, which was prevented by treatment with AG1478, AG825 (ErbB2 inhibitor) and with genistein, further suggesting a role for EGFR and ErbB2. Response to the endothelium-independent vasodilator sodium nitroprusside remained normal in tissue from STZ-diabetic animals, suggesting a dysfunction at the level of the endothelium. Studies in human endothelial-like ECV-304 cells grown in high glucose also showed alterations in EGFR and ErbB2 signalling. Glucose-induced upregulation of pEGFR and pErbB2 levels were accompanied by increased phosphorylation of the downstream molecule PKC and of eNOS at threonine 495, which inactivates the molecule and reduces NO production. Studies using isolated rat aortic tissue revealed that EGF has a vasodilator effect in endothelium-intact tissue but a vasoconstrictive effect in endothelium-denuded tissue. These studies along with cell culture studies also suggest that glucose changes EGFR signalling properties from it mediating a pro-relaxant effect in normal glucose to produce a pro-contractile effect in high glucose conditions. These results suggest an important role for EGFR, ErbB2 and PKC signalling in mediating diabetes-induced vascular dysfunction, and as such may represent novel therapeutic targets.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:584252 |
| Date | January 2008 |
| Creators | Griffiths, Sioned Mai |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/54092/ |
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