Vascular endothelial growth factor vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin
Vascular endothelial growth factor vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin
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DOI：
10.1161/01.cir.97.1.99
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发表时间：
1998-01-01
期刊：
影响因子：
37.8
通讯作者：
Isner, JM
中科院分区：
文献类型：
--
作者：
Murohara, T;Horowitz, JR;Isner, JM
血管内皮生长因子（VEGF）是一种促进血管生成的内皮细胞有丝分裂原，最初被鉴定为血管通透性因子（VPF）。大量证据表明，血管生成之前和/或伴随着微血管通透性的增强。然而，VEGF/VPF增加血管渗透性（VP）的机制仍然是个谜，因此，我们使用VP的体内测定（Miles测定）来研究VEGF/VPF诱导的渗透性的推定介质。方法和结果--VEGF/VPF和阳性对照（血小板激活因子[PAF]）。组胺和缓激肽）均增加血管通透性。酪氨酸激酶抑制剂染料木黄酮或除莠霉素A预先给药阻止VEGF/VPF诱导的渗透性。胎盘生长因子与Flt-1/VEGF-R1结合，但不与Flk-1/KDR/VEGF-R2受体酪氨酸激酶结合，未能增加通透性。其他生长因子如碱性成纤维细胞生长因子（FGF）、酸性FGF、血小板衍生生长因子-BB、转化生长因子-β、分散因子和粒细胞巨噬细胞集落刺激因子（8 - 128 ng）未能增加渗透性。VEGF/VPF诱导的渗透性被一氧化氮（NO）合酶抑制剂N-ω-硝基-L-精氨酸（10 mg/kg）或N-ω-硝基-L-精氨酸甲酯（20 mg/kg）和环氧合酶抑制剂吲哚美辛（5 mg/kg）显著减弱。无活性对映体N-ω-硝基-D-精氨酸甲酯（20 mg/kg）不抑制VEGF/VPF诱导的渗透性。体外研究证实，VEGF/VPF刺激微血管内皮细胞合成NO和前列腺素代谢产物。最后，NO供体和前列环素类似物他前列烯一起给药，但不是单独复制VEGF/VPF. Conclusions观察到的渗透性的增加，这些结果牵连NO和前列环素产生的相互作用的VEGF/VPF与其Flk-1/KDR/VEGF-R2受体作为介导的VEGF/VPF诱导的血管通透性。此外，在血管生成细胞因子中，这种性质似乎是VEGF/VPF所独有的。
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.