Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus

Vascular complications such as foot ulcers are a hallmark of diabetes mellitus (DM), although the molecular mechanisms that underlie vascular dysfunction remain unclear. Herein, we show that angiogenesis, which is indispensable to the healing of ulcers, is suppressed in polyurethane sponge implants in mice with DM and reduced proangiogenic signaling. DM was induced in male C57BL/6 mice by intraperitoneal injection of streptozotocin (100 mg/kg). Polyurethane sponge disks were implanted into subcutaneous tissues on the backs of mice, and angiogenesis and expression of related factors were analyzed in sponge granulation tissues. Densities of platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive vascular structures and PECAM-1 expression in sponge granulation tissues were increased over time in control mice and reduced in diabetic mice. The reductions in diabetic mice were accompanied by reduced expression of inducible cyclo-oxygenase-2 and microsomal prostaglandin E synthase-1. The prostaglandin E receptor subtype EP3 was downregulated in sponge granulation tissues in diabetic mice, whereas EP1, EP2, and EP4 were not. The expression of the proangiogenic growth factor vascular endothelial growth factor (VEGF)-A and the chemokine stromal cell-derived factor-1 (SDF-1) were both reduced in diabetic mice. Treatment of diabetic mice with a selective agonist of EP3, ONO-AE 248 (30 nmol/site/day, topical injection), reversed suppression of angiogenesis in diabetic mice. These results indicate that proangiogenic EP3 signaling is suppressed in diabetic mice with reduced expression of VEGF and SDF-1. Stimulation of EP3 signaling restored angiogenesis in a sponge implant model in mice with DM. This suggests that topical application of an EP3 agonist could be a novel strategy to treat foot ulcers in patients with DM.