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Vascular permeability induced by VEGF family members in vivo: Role of endogenous PAF and NO synthesis
Author(s) -
Brkovic Alexandre,
Sirois Martin G.
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21124
Subject(s) - vascular permeability , extravasation , enos , vascular endothelial growth factor , nitric oxide , chemistry , endocrinology , vascular endothelial growth factor a , medicine , sodium nitroprusside , pharmacology , platelet activating factor , nitric oxide synthase , biology , immunology , vegf receptors
We previously reported that vascular endothelial growth factor (VEGF) increases vascular permeability through the synthesis of endothelial platelet‐activating factor (PAF), while others reported the contribution of nitric oxide (NO). Herein, we addressed the contribution of VEGF receptors and the role played by PAF and NO in VEGF‐induced plasma protein extravasation. Using a modified Miles assay, intradermal injection in mice ears of VEGF‐A 165 , VEGF‐A 121 , and VEGF‐C (1 µM) which activate VEGFR‐2 (Flk‐1) receptor increased vascular permeability, whereas a treatment with VEGFR‐1 (Flt‐1) analogs; PlGF and VEGF‐B (1 µM) had no such effect. Pretreatment of mice with PAF receptor antagonist (LAU8080) or endothelial nitric oxide synthase (eNOS) inhibitor ( L ‐NAME) abrogated protein extravasation mediated by VEGF‐A 165 . As opposed to PAF (0.01‐1 µM), treatment with acetylcholine (ACh; up to 100 µM; inducer of NO synthesis) or sodium nitroprusside (SNP; up to 1 µM; NO donor) did not induce protein leakage. Simultaneous pretreatment of mice with eNOS and protein kinase A (PKA) inhibitors restored VEGF‐A 165 vascular hyperpermeability suggesting that endogenous NO synthesis leads to PKA inhibition, which support maintenance of vascular integrity. Our data demonstrate that VEGF analogs increase vascular permeability through VEGFR‐2 activation, and that both endogenous PAF and NO synthesis contribute to VEGF‐A 165 ‐mediated vascular permeability. However, PAF but not NO directly increases vascular permeability per se, thereby, suggesting that PAF is a direct inflammatory mediator, whereas NO serves as a cofactor in VEGF‐A 165 proinflammatory activities. J. Cell. Biochem. 100: 727–737, 2007. © 2006 Wiley‐Liss, Inc.