Epidermal growth factor receptor tyrosine kinase-mediated signalling contributes to diabetes-induced vascular dysfunction in the mesenteric bed

Abstract

In order to characterize the roles of tyrosine kinases (TKs) and epidermal growth factor receptor (EGFR) in diabetes-induced vascular dysfunction, we investigated the ability of a chronic administration of genistein, a broad-spectrum inhibitor of TKs and AG1478, a specific inhibitor of EGFR TK activity to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes in rats. The vasoconstrictor responses induced by norepinephrine (NE), endothelin-1 (ET-1) and angiotensin II (Ang II), were significantly increased, whereas vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of STZ-induced diabetic rats in comparison with healthy rats. Treatment of diabetic animals with genistein or AG1478 produced a significant normalization of the altered agonist-induced vasoconstrictor and vasodilator responses without affecting blood glucose levels. In contrast, neither inhibitor had any effect on the vascular responsiveness of control (nondiabetic) animals. Treatment of diabetic animals with diadzein, an inactive analogue of genistein, did not affect the vasoconstrictor and vasodilator responses in control or diabetic animals. Phosphorylated EGFR levels were markedly raised in the mesenteric bed from diabetic animals and were normalized upon treatment with AG1478 or genistein. These data suggest that activation of TK-mediated pathways, including EGFR TK signalling are involved in the development of diabetic vascular dysfunction. © 2005 Nature Publishing Group. All rights reserved.