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

  1. Pedro Geraldes1,*
  1. 1From the Clinical Research Center Étienne Le-Bel and Departments of Medicine, Division of Endocrinology, Université de 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 the diabetic peripheral limbs is characterised 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 VEGF and PDGF. The present study investigates the role of PKCδ in diabetes-induced poor collateral vessel formation and inhibition of angiogenic factors expression and actions. Ischemic adductors muscles of diabetic Prkcd+/+ mice exhibited reduced blood reperfusion, vascular density and number of small vessels as compared to non-diabetic Prkcd+/+ mice. By contrast, diabetic Prkcd-/- mice showed significant increased blood flow, capillary density and number of capillaries. Although expression of various PKC isoforms were unchanged, activation of PKCδ was increased in diabetic Prkcd+/+ mice. VEGF and PDGF mRNA and protein expression were decreased in muscles of diabetic Prkcd+/+ mice and normalized in diabetic Prkcd-/- mice. Furthermore, phosphorylation of VEGFR2 and 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.

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

This Article

  1. Diabetes
  1. Supplementary Data
  2. All Versions of this Article:
    1. db12-1432v1
    2. 62/8/2948 most recent