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

Abstract

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

Hypoxic Preconditioning Augments Efficacy of Human Endothelial Progenitor Cells for Therapeutic Neovascularization

“…VEGF elicits the angiogenic function in ECs mainly through the receptor tyrosine kinase KDR/ Flk-1. That is, VEGF induces EC proliferation and increases vascular permeability mainly via the KDR/ Flk-1 (Kanno et al, 2000;Millauer et al, 1993;Murohara et al, 1998b). In the present study, the neutralizing anti-VEGF mAb, the tyrosine kinase inhibitor genistein, and the KDR-specific tyrosine kinase inhibitor SU1498 all inhibited the differentiation of PB-MNCs into EPCs.…”

The Role of Vascular Endothelial Growth Factor in Wound Healing

“…A unique property of VEGF is its ability to increase vascular permeability 65 . Before its amino acid sequence was known, VEGF was designated vascular permeability factor (VPF).…”

“…VEGF is more potent than histamine in inducing vascular leakage 17,20,21 . It binds to the KDR receptor, stimulating nitric oxide synthase (NOS) and cyclooxygenase activities 65 . NO and prostacyclin promote simultaneous vasodilation and vascular permeability 66,67 .…”

VEGF Receptor Signaling and Endothelial Function

“…VEGF-A and VEGF-E stimulates endothelial production of NO and prostacyclin (57,74,(89)(90)(91)(92)(93). In turn, these intracellular mediators have been implicated in mediating diverse biological effects of VEGF including angiogenesis and vascular permeability (94).…”