Introduction: Ischemia due to narrowing of the femoral artery and distal vessels is also a major cause of peripheral arterial disease and morbidity affecting patients with diabetes. Our laboratory has previously shown that hyperglycemia reduced vascular endothelial growth factor receptor (VEGFR2) activity in ischemic muscle of diabetic mice, which was not observed in protein kinase C (PKC)-Δ deficient mice. The objective of this study is to evaluate the impact of a specific deletion of PKC-Δ in endothelial cells in diabetic mice.

Methods: Nondiabetic (NDM) and 3 months diabetic (DM) mice with deletion of PKC-Δ specifically in endothelial cells (PrckdEC-) were used. Ligation of the femoral artery was performed and blood flow reperfusion was measured by laser Doppler for 4 weeks. Primary lung endothelial cells (EC) isolated from each group of mice were exposed to normal (5.6mM; NG) or high glucose concentrations (25mM; HG) for 48 hours, in normoxia (20% oxygen) or hypoxia (1%) for the last 24 hour in presence of VEGF, a pro-angiogenic factor.

Results: Blood flow was recovered to 43% in DM mice compared to 78% in NDM mice. Specific EC deletion of PKC-Δ enhanced reperfusion in NDM and DM mice up to 88% and 71%, respectively. Expression of VEGFR2 was decreased in ischemic muscle of DM mice, but not in DM-PrkcdEC- mice. In vitro, VEGF-induced Akt phosphorylation was reduced by 40% in EC isolated from DM mice compared to NDM mice, which was prevented in EC isolated from DM-PrkcdEC- exposed to HG+hypoxia.

Conclusion: Diabetes induced PKC-Δ activity and caused inhibition of VEGF actions in EC, whereas the deletion of PKC-Δ specifically in EC restored VEGF action, VEGFR2 expression and blood flow reperfusion in diabetic mice.


P. Geraldes: None.

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