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(Circulation. 1998;97:99-107.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Vascular Endothelial Growth Factor/Vascular Permeability Factor Enhances Vascular Permeability Via Nitric Oxide and Prostacyclin

Toyoaki Murohara, MD; Jeffrey R. Horowitz, BS; Marcy Silver, BS; Yukio Tsurumi, MD; Dongfen Chen, MD; Alison Sullivan, MS; ; Jeffrey M. Isner, MD

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-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.

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.

Key Words: endothelium • growth substances • nitric oxide • prostaglandins • permeability

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				H. Lim, R. A. Gupta, W.-g. Ma, B. C. Paria, D. E. Moller, J. D. Morrow, R. N. DuBois, J. M. Trzaskos, and S. K. Dey Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta Genes & Dev., June 15, 1999; 13(12): 1561 - 1574. [Abstract] [Full Text]

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				H. Gille, J. Kowalski, B. Li, J. LeCouter, B. Moffat, T. F. Zioncheck, N. Pelletier, and N. Ferrara Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A REASSESSMENT USING NOVEL RECEPTOR-SPECIFIC VASCULAR ENDOTHELIAL GROWTH FACTOR MUTANTS J. Biol. Chem., January 26, 2001; 276(5): 3222 - 3230. [Abstract] [Full Text] [PDF]

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				H. Matsushita, E. Chang, A. J. Glassford, J. P. Cooke, C.-P. Chiu, and P. S. Tsao eNOS Activity Is Reduced in Senescent Human Endothelial Cells: Preservation by hTERT Immortalization Circ. Res., October 26, 2001; 89(9): 793 - 798. [Abstract] [Full Text] [PDF]