Deletion of AT2 Receptor Prevents SHP-1–Induced VEGF Inhibition and Improves Blood Flow Reperfusion in Diabetic Ischemic Hindlimb

Abstract

Our results suggest that the deletion of AT2 receptor reduced SHP-1 activity and restored VEGF actions, leading to an increased blood flow reperfusion after ischemia in diabetes mellitus.

Ablation of angiotensin type 2 receptor prevents endothelial nitric oxide synthase glutathionylation and nitration in ischaemic abductor muscle of diabetic mice

“…10 Our previous study showed that the phosphorylation of the VEGFR2, and subsequently Akt was reduced in diabetic animals and completely prevented in the muscle of Agtr2 −/Y mice 4 weeks post surgery. 13 This study enhanced our knowledge that AT2R activation can also affect eNOS in vivo by decreasing both the phosphorylation and expression of eNOS. Numerous studies reported compelling evidence that eNOS uncoupling, which is characterized by the generation of superoxide instead of NO, has been viewed has an important mechanism of endothelial dysfunction in diabetes.…”

“…3,18 We have recently reported that diabetes-induced AT2R activation led to increased SHP-1 activity and reduced VEGF actions in the ischaemic muscle after 4 weeks of femoral artery ligation. Since we observed that blood flow reperfusion was almost completely restored after 2 weeks following ischaemia, 13 this study investigated the effect of AT2R ablation on neovascularization in the ischaemic hindlimb in diabetic mice after 14 days post surgery. Deletion of AT2R significantly prevented endothelial cell death in the ischaemic muscle of diabetic mice as compared to diabetic Agtr2 +/Y mice.…”

“…C57BL/6J ( Ins2 +/+ ) and diabetic heterozygous male Ins2 +/C96Y (diabetes mellitus (DM); Akita) mice were purchased from The Jackson Laboratory and bred with the Agtr2 −/Y mice in our animal facility for seven generations as described previously. 13 Each group included 12 mice. Throughout the entire study, animals were provided with free access to water and standard rodent chow (Harlan Teklad).…”

“…12 In the context of diabetes, our group has recently published that activation of AT2R prevented VEGF actions on endothelial cell proliferation and migration. 13 This inhibition was associated with down regulation of ischaemia-induced angiogenesis caused by elevated expression of SHP-1. Interaction between AT2R/SHP-1 and VEGF signalling pathway has been demonstrated 4 weeks post ligation of the femoral artery.…”

Renin-Angiotensin System and Cardiovascular Functions

“…Depletion of AT2 receptor augmented blood flow reperfusion and collateral vessel formation that were associated with SH2 domain-containing phosphatase 1 activity and vascular endothelial growth factor action. 179 …”