455-P: Pan-ErbB Inhibition Attenuates Diabetes-Induced Vascular Dysfunction in an Experimental Model of Diabetes

The underlying mechanisms leading to diabetes-induced vascular complications are not fully understood. We have previously shown that epidermal growth factor receptor (EGFR), which is part of the four membered family of EGFR/ErbB receptor tyrosine kinases, appears to play a detrimental role. However, the role of the other ErbB family members (ErbB2, ErbB3, and ErbB4)- that regulate cell growth, proliferation, differentiation and apoptosis- is not fully known and was further evaluated in this study. In a streptozotocin-rat model of type 1 diabetes, 4-weeks of diabetes induced significant vascular dysfunction, as assessed by abnormally high vasoconstrictor responses to norepinephrine in the mesenteric vascular bed (MVB). Diabetes also led to increased phosphorylation of all ErbB receptors with subsequent increased phosphorylation of downstream ERK1/2 in the MVB. Chronic 4-week in vivo administration of a novel pan-ErbB inhibitor, generation 7 polyamidoamine dendrimer (G7PAMAM; 20mg/kg daily i.p), or the well-established pan-ErbB inhibitor, Genistein (1mg/kg i.p. alt diem) to diabetic rats led to a marked attenuation in the hyperphosphorylation of all ErbBs, ERK1/2 and to a significant correction in NE-mediated hyper-responsiveness of the diabetic MVB. Furthermore, pan-ErbB inhibitors attenuated high glucose-induced ErbBs-ERK1/2 signaling in primary vascular smooth muscle cells grown in high (25mM) glucose. These data show for the first time that pan-ErbB inhibition attenuates diabetes-induced vascular dysfunction in an experimental model of diabetes. Therefore, pan-ErbB inhibition might represent a novel strategy for the treatment of diabetes-induced vascular complications.