Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin.

Circulation 1998 Jan 6-13;97(1):99-107

Department of Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.

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-beta, 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(omega)-nitro-L-arginine (10 mg/kg) or N(omega)-nitro-L-arginine methyl ester (20 mg/kg) and the cyclooxygenase inhibitor indomethacin (5 mg/kg). The inactive enantiomer N(omega)-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.

Download full-text PDF

Source
http://dx.doi.org/10.1161/01.cir.97.1.99DOI Listing
February 1998
3 Reads

Publication Analysis

Top Keywords

vascular permeability
20
permeability
13
growth factor
12
vegf/vpf-induced permeability
12
increase permeability
12
ester mg/kg
8
nitric oxide
8
mediators vegf/vpf-induced
8
tyrosine kinase
8
methyl ester
8
failed increase
8
flk-1/kdr/vegf-r2 receptor
8
factor
8
vascular endothelial
8
permeability factor
8
endothelial growth
8
vascular
7
growth
7
vegf/vpf
5
vegf/vpf-induced
5

Altmetric Statistics

References

(Supplied by CrossRef)

J Immunol 1994

Am J Pathol 1995

Am J Pathol 1996

Similar Publications