Upregulation of epidermal growth factor receptor (EGFR) signaling is involved in development of diabetes-induced vascular dysfunction. Polyamidoamine (PAMAM) dendrimers (branch-like polymers) might be novel inhibitors of EGFR for they inhibit EGFR phosphorylation in vitro. Here, we investigated whether chronic administration of a generation (G) 7 PAMAM dendrimer could have beneficial effects on diabetes-induced vascular dysfunction by inhibiting EGFR signaling in a model of type 1 diabetes. Dendrimer administration (daily i.p for up to 4 weeks) to Male Wistar rats bearing streptozotocin-induced diabetes dose- and time-dependently inhibited EGFR-ERK1/2-ROCK signaling- a key pathway in the development of diabetic vascular complications. Dendrimer-induced inhibition of EGFR signaling correlated well with a significant correction in hyper-responsiveness of the diabetic mesenteric vascular bed to norephinephrine- a routinely used experimental measure of vascular dysfunction. The dendrimer also inhibited high glucose-induced EGFR-ERK1/2-ROCK signaling in primary vascular smooth muscle cells grown in high (25mM) glucose. These data show for the first time that a PAMAM dendrimer administered chronically in vivo can lead to inhibition of EGFR-ERK1/2-ROCK signaling and attenuate diabetes-induced vascular dysfunction in an experimental model of diabetes.
S. Akhtar: None. B. Chandrasekhar: None. A.Z. El-Hashim: None. I. Benter: None.