PKCδ impaired vessel formation and angiogenic factor expression in diabetic ischemic limbs

Area of Science:

• Vascular biology
• Diabetes research
• Molecular medicine

Background:

• Diabetes mellitus is associated with impaired collateral vessel formation in peripheral limbs, a process crucial for tissue reperfusion after ischemia.
• Hyperglycemia in diabetes activates protein kinase C (PKC), which can negatively impact angiogenic growth factors like vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

Purpose of the Study:

• To investigate the specific role of PKCδ in diabetes-induced defects in collateral vessel formation.
• To elucidate the mechanisms by which PKCδ affects the expression and activity of key angiogenic factors and their receptors.

Main Methods:

• Comparison of ischemic adductor muscle function and vascularization in diabetic and non-diabetic mice with and without the Prkcd gene (Prkcd(+/+) vs. Prkcd(-/-)).
• Assessment of blood reperfusion, vascular density, and vessel counts.
• Measurement of VEGF and PDGF mRNA and protein expression.
• Analysis of phosphorylation status of VEGF receptor 2 (VEGFR2) and PDGF receptor-β (PDGFR-β).
• Evaluation of SHP-1 expression levels.

Main Results:

• Diabetic Prkcd(+/+) mice showed reduced blood reperfusion and vascular density compared to non-diabetic controls.
• Diabetic Prkcd(-/-) mice exhibited significantly improved blood flow, capillary density, and vessel counts.
• PKCδ activation was increased in diabetic Prkcd(+/+) mice, while VEGF and PDGF expression and VEGFR2/PDGFR-β phosphorylation were decreased.
• These inhibitory effects were reversed in diabetic Prkcd(-/-) mice, with normalization of growth factor expression and receptor activity.
• Increased SHP-1 expression was linked to the inhibition of VEGFR2 and PDGFR-β activity.

Conclusions:

• PKCδ activation is a key mechanism underlying impaired collateral vessel formation in diabetic peripheral limbs.
• Targeting PKCδ may offer a novel therapeutic strategy to enhance angiogenesis and improve outcomes in diabetic patients with peripheral vascular disease.