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  • Title: Differential regulation of VEGF signaling by PKC-alpha and PKC-epsilon in endothelial cells.
    Author: Rask-Madsen C, King GL.
    Journal: Arterioscler Thromb Vasc Biol; 2008 May; 28(5):919-24. PubMed ID: 18323518.
    Abstract:
    OBJECTIVE: Vascular endothelial growth factor (VEGF) stimulates proangiogenic signal transduction and cell function in part through activation of protein kinase C (PKC). Our aim was to examine how individual isoforms of PKC affect VEGF action. METHODS AND RESULTS: Transfection of bovine aortic endothelial cells with small interfering RNA (siRNA) targeting either PKC-alpha, delta, or epsilon caused a reduction in the cognate PKC protein by 76% to 89% without changing expression of nontargeted isoforms. Downregulation of PKC-epsilon abrogated VEGF-stimulated phosphorylation of Akt at Ser473 and eNOS at Ser1179 and decreased VEGF-stimulated NO synthase activity in intact cells. In contrast, PKC-alpha knockdown increased Akt and eNOS phosphorylation, whereas PKCdelta knockdown had no significant effect. PKC-epsilon knockdown also decreased VEGF-stimulated Erk1/2 phosphorylation and abolished VEGF-stimulated DNA synthesis. Consistent with an effect on several pathways of VEGF signaling, VEGF receptor-2 (VEGFR2) tyrosine phosphorylation and expression of VEGFR2 protein and mRNA was decreased by 81, 90, and 84%, respectively, during knockdown of PKC-epsilon, but increased during PKC-alpha knockdown. CONCLUSIONS: By regulating VEGFR2 expression and activation, PKC-epsilon expression is critical for activation of Akt and eNOS by VEGF and contributes to VEGF-stimulated Erk activation, whereas PKC-alpha has opposite effects.
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