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


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.
Murohara
T
T
Department of Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Horowitz
J R
JR
Silver
M
M
Tsurumi
Y
Y
Chen
D
D
Sullivan
A
A
Isner
J M
JM
D000818:Animals; D016227:Benzoquinones; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D009573:Nitrites / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011726:Pyridinium Compounds / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016227:Benzoquinones; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D047029:Lactams, Macrocyclic; D008222:Lymphokines; D009573:Nitrites; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; D011809:Quinones; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C053321:CV 6209; D017828:Rifabutin; D010656:Phenylephrine; D009569:Nitric Oxide; D005346:Fibroblast Growth Factors; C020754:herbimycin; D006632:Histamine; D011464:Epoprostenol; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester