FIGURE 2.

A schematic of the likely signaling effectors of EGFR/ErbB receptors in mediating diabetes-induced vascular dysfunction. Although there is now evidence that all four ErbB receptors may be activated by hyperglycemia, the majority of the data suggests that diabetes induced vascular dysfucntion proceeds via phosphorylation and subsequent hetero-dimerization EGFR and ErbB2 receptors. This is turn begins a cascade of downstream signaling pathways including attenuation of eNOS that results in decreased NO production. Activation of P13K, such as by green tea components like catechin, can rescure eNOS and reduction in NO. eNOS appears to be upstream of NF-kB activation. Additionally, ERK1/2 activation leads to downstream ROCK signaling–a key driver of pro-contractile changes leading to vascular dysfunction. Interestingly, activation of AKT and FOXO occur independently of each other implying that uncoupling of AKT-FOXO axis is a key component in developing diabetes-induced vascular complications. There is also evidence that EGFR/ErbB2 signaling via NADPH-oxidase (NOX) leads to increased ROS/oxidative and ER stress in the diabetic cardiovascular system. The precise cross-talk and interplay between these and other pathways remains to be fully elucidated. Furthermore, since multiple gene expression changes are known to corrected by EGFR inhibition in the diabetic vasculature, it is very likely that the signaling pathways discussed here will act in concert with multiple other, as yet unconfirmed, signaling cascades that are downstream of EGFR/ErbB receptors to eventually lead to diabetes-induced vascular cell apoptosis and dysfunction. Some of the reported pharmacologic interventions used in the analyses of these pathways are also shown; red dead-end arrow indicates inhibition; green arrow indicates activation (refer to the main text for more details and references).