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 Blood, 8 October 2009, Vol. 114, No. 15, pp. 3343-3351.
Prepublished online as a Blood First Edition Paper on June 29, 2009; DOI 10.1182/blood-2008-12-196584.

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VASCULAR BIOLOGY

Phosphorylation of endothelial nitric oxide synthase by atypical PKC{zeta} contributes to angiopoietin-1–dependent inhibition of VEGF-induced endothelial permeability in vitro

Malika Oubaha1, and Jean-Philippe Gratton1

1 Laboratory of Endothelial Cell Biology, Institut de Recherches Cliniques de Montréal, Université de Montréal, Montreal, QC

Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine that also increases vascular permeability. Nitric oxide (NO) released from endothelial cells, after activation of endothelial NO synthase (eNOS), contributes to proangiogenic and permeability effects of VEGF. Angiopoietin-1 (Ang-1), via Tie2 receptors, shares many of the proangiogenic properties of VEGF on endothelial cells. However, in contrast to VEGF, Ang-1 protects blood vessels from increased plasma leakage, which contributes to their stabilization. Because eNOS-derived NO is central to increased permeability in response to VEGF, we investigated whether Ang-1 interferes with VEGF signaling to eNOS. We demonstrate that Ang-1 stimulation of endothelial cells inhibits VEGF-induced NO release and transendothelial permeability. In contrast to VEGF stimulation, Ang-1 causes a marked protein kinase C (PKC)–dependent increase in phosphorylation of eNOS on the inhibitory Thr497. Furthermore, using pharmacologic inhibitors, overexpression studies, and small interfering RNA-mediated gene silencing, we demonstrate that atypical PKC{zeta} is responsible for phosphorylation of eNOS on Thr497 in response to Ang-1. In addition, PKC{zeta} knockdown abrogates the capacity of Ang-1 to inhibit VEGF-induced NO release and endothelial permeability. Thus, inhibition of NO production by Ang-1, via phosphorylation of eNOS on Thr497 by PKC{zeta}, is responsible, at least in part, for inhibition of VEGF-stimulated endothelial permeability by Ang-1.


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