Délétion endothéliale de SHP-1 prévient la sénescence et rétablit l’angiogenèse des cellules endothéliales vasculaires en condition de diabète
Diabetes causes a dysregulation of angiogenesis, an essential process for the formation of new blood vessels following ischemia, and enhances vascular ageing (senescence), increasing the risk of amputation for patients with diabetes. Our laboratory has shown that the increased expression of protein tyrosine phosphatase SHP-1 in the ischemic muscle of diabetic mice was associated with higher phosphatase activity in the endothelial cells (EC) exposed to high concentrations of glucose. Our objective was to evaluate the role of SHP-1 in the regulation of the angiogenic process and senescence in the EC and ischemic muscle of diabetic mice. Diabetic (DM) and non-diabetic (NDM) mice with or without EC-specific deletion of SHP-1 underwent femoral artery ligation. Blood reperfusion was measured over a 4-week period using Doppler laser imaging and muscles were harvested for protein analysis. Histological staining was also performed in the ischemic muscle of all groups of mice. In vitro, EC were exposed to normal (5.6 mM; NG) or high (25 mM; HG) glucose concentrations and placed under a hypoxic environment (1% O2) in the presence or absence of the angiogenic factor VEGF (10 ng/mL) with or without overexpression of dominant negative of SHP-1. Four weeks after surgery, blood reperfusion, limb function (distance traveled in a running wheel) and formation of new collateral vessels in ischemic muscle were significantly reduced in DM mice compared to NDM mice. These effects of diabetes were prevented by the EC-specific deletion of SHP-1. In vitro, the use of a dominant negative SHP-1 reversed HG-induced inhibition of VEGF actions in EC by restoring phosphorylation of VEGFR-2 and Akt. Meanwhile, inhibition of SHP-1 prevented the increased expression of p21 and β-galactosidase as well as the reduction of Nrf2, three senescence markers, caused by HG exposure. In conclusion, EC-specific deletion of SHP-1 prevented the effects of diabetes on senescence and angiogenesis leading to improved blood reperfusion and limb function in diabetic mice.
Maladie des artères périphériques, Diabète, Sénescence, Angiogenèse, SHP-1, VEGF, p21, Peripheral arterial disease, Diabetes, Senescence, Angiogenesis
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