title: PKCδ impaired vessel formation and angiogenic factor expression in diabetic ischemic limbs.
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.
authors.affiliation: Clinical Research Center Étienne Le-Bel and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Farah
authors.initials: F
authors.lastname: Lizotte
authors.forename: Martin
authors.initials: M
authors.lastname: Paré
authors.forename: Benoit
authors.initials: B
authors.lastname: Denhez
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Andréanne
authors.initials: A
authors.lastname: Guay
authors.forename: Pedro
authors.initials: P
authors.lastname: Geraldes
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015424:Reperfusion; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D051745:Protein Kinase C-delta
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