From the Departments of Medicine (Cardiology) and Biomedical Research, St
Elizabeth's Medical Center, Tufts University School of Medicine, Boston,
Mass.
Correspondence to Jeffrey M. Isner, MD, Department of Cardiology, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135.
Background—Vascular
endothelial growth factor (VEGF), an
endothelial cell mitogen that promotes angiogenesis,
was initially identified as a vascular permeability factor (VPF).
Abundant evidence suggests that angiogenesis is preceded and/or
accompanied by enhanced microvascular permeability. The mechanism by
which VEGF/VPF increases vascular permeability (VP), however, has
remained enigmatic. Accordingly, we used an in vivo assay of VP (Miles
assay) to study the putative mediators of VEGF/VPF-induced
permeability.
Methods and Results—VEGF/VPF and positive controls
(platelet-activating factor [PAF], histamine, and bradykinin) all
increased vascular permeability. Prior administration of the tyrosine
kinase inhibitors genistein or herbimycin A prevented
VEGF/VPF-induced permeability. Placenta growth factor, which binds to
Flt-1/VEGF-R1 but not Flk-1/KDR/VEGF-R2
receptor tyrosine kinase, failed to increase permeability. Other growth
factors such as basic fibroblast growth factor (FGF), acidic FGF,
platelet-derived growth factor-BB, transforming growth factor-ß,
scatter factor, and granulocyte macrophage-colony stimulating
factor (8 to 128 ng) failed to increase permeability. VEGF/VPF-induced
permeability was significantly attenuated by the nitric oxide (NO)
synthase inhibitors
N
Conclusions—These results implicate NO and prostacyclin produced
by the interaction of VEGF/VPF with its
Flk-1/KDR/VEGF-R2 receptor as mediators of
VEGF/VPF-induced vascular permeability. Moreover, this property appears
unique to VEGF/VPF among angiogenic cytokines.
© 1998 American Heart Association, Inc.
Basic Science Reports
Vascular Endothelial Growth Factor/Vascular Permeability Factor Enhances Vascular Permeability Via Nitric Oxide and Prostacyclin
-nitro-L-arginine (10 mg/kg)
or N-nitro-L-arginine methyl
ester (20 mg/kg) and the cyclooxygenase
inhibitor indomethacin (5 mg/kg). The
inactive enantiomer
N-nitro-D-arginine methyl
ester (20 mg/kg) did not inhibit VEGF/VPF-induced permeability. In
vitro studies confirmed that VEGF/VPF stimulates synthesis of NO and
prostaglandin metabolites in microvascular
endothelial cells. Finally, NO donors and the
prostacyclin analogue taprostene administered together but not alone
reproduced the increase in permeability observed with VEGF/VPF.
Key Words: endothelium • growth substances • nitric oxide • prostaglandins • permeability
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