Opposite effects of angiotensins receptors type 2 and type 4 on streptozotocin induced diabetes vascular alterations in mice

BACKGROUND: We examined the effect of chronic administration of angiotensin IV (AngIV) on the vascular alterations induced by type 1 diabetes in mice. METHODS: Diabetes was induced in adult Swiss mice with a single injection of streptozotocin (STZ). Mice were treated subcutaneously with AngIV (1.4 mg/kg/day) either immediately following diabetes induction (preventive treatment), or treated with AngIV (0.01 to 1.4 mg/kg), alone or with the AT4 receptor antagonist Divalinal or the AT2 receptor antagonist PD123319, for two weeks after 4 weeks of diabetes duration (rescue treatment). Acetylcholine-induced, endothelium-dependent relaxation (EDR) was measured in isolated aortic rings preparations. Histomorphometric measurements of the media thickness were obtained, and nitric oxide (NO) and superoxide anion production were measured by electron paramagnetic resonance in aorta and mesenteric arteries. The effect of diabetes on mesenteric vascular alterations was also examined in genetically modified mice lacking the AT2 receptor. RESULTS: Induction of diabetes with STZ was associated with a progressive decrease of EDR and an increase of the aortic and mesenteric media thickness already significant after 4 weeks and peaking at week 6. Immediate treatment with AngIV fully prevented the diabetes-induced endothelial dysfunction. Rescue treatment with AngIV implemented after 4 weeks of diabetes dose-dependently restored a normal endothelial function at week 6. AngIV blunted the thickening of the aortic and mesenteric media, and reversed the diabetes-induced changes in NO and O2•- production by the vessels. The protective effect of AngIV on endothelial function was completely blunted by cotreatment with Divalinal, but not with PD123319. In contrast, both the pharmacological blockade and genetic deletion of the AT2 receptor reversed the diabetes-induced morphologic and endothelial alteration caused by diabetes. CONCLUSIONS: The results suggest an opposite contribution of AT2 and AT4 receptors to the vascular alterations caused by streptozotocin-induced diabetes in mice, since chronic stimulation of AT4 by AngIV and inhibition of AT2 similarly reverse diabetes-induced endothelial dysfunction and hypertrophic remodeling, and increase NO bioavailability.