PKCδ Impaired Vessel Formation and Angiogenic Factor Expression in Diabetic Ischemic Limbs

  1. Pedro Geraldes1
  1. 1Clinical Research Center Étienne Le-Bel and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
  2. 2The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
  1. Corresponding author: Pedro Geraldes, pedro.geraldes{at}usherbrooke.ca.

Abstract

Decreased collateral vessel formation in diabetic peripheral limbs is characterized by abnormalities of the angiogenic response to ischemia. Hyperglycemia is known to activate protein kinase C (PKC), affecting the expression and activity of growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The current study investigates the role of PKCδ in diabetes-induced poor collateral vessel formation and inhibition of angiogenic factors expression and actions. Ischemic adductor muscles of diabetic Prkcd+/+ mice exhibited reduced blood reperfusion, vascular density, and number of small vessels compared with nondiabetic Prkcd+/+ mice. By contrast, diabetic Prkcd−/− mice showed significant increased blood flow, capillary density, and number of capillaries. Although expression of various PKC isoforms was unchanged, activation of PKCδ was increased in diabetic Prkcd+/+ mice. VEGF and PDGF mRNA and protein expression were decreased in the muscles of diabetic Prkcd+/+ mice and were normalized in diabetic Prkcd−/− mice. Furthermore, phosphorylation of VEGF receptor 2 (VEGFR2) and PDGF receptor-β (PDGFR-β) were blunted in diabetic Prkcd+/+ mice but elevated in diabetic Prkcd−/− mice. The inhibition of VEGFR2 and PDGFR-β activity was associated with increased SHP-1 expression. In conclusion, our data have uncovered the mechanisms by which PKCδ activation induced poor collateral vessel formation, offering potential novel targets to regulate angiogenesis therapeutically in diabetic patients.

Footnotes

  • Received October 16, 2012.
  • Accepted March 29, 2013.

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  1. Diabetes vol. 62 no. 8 2948-2957
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