Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells (Retracted article. See vol. 31, pg. 421, 2017)
Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells (Retracted article. See vol. 31, pg. 421, 2017)
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DOI：
10.1096/fj.06-7854com
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发表时间：
2007-08-01
期刊：
影响因子：
4.8
通讯作者：
Caldwell, R. B.
中科院分区：
文献类型：
--
作者：
El-Remessy, A. B.;Al-Shabrawey, M.;Caldwell, R. B.
活性氧（ROS）对血管生成信号的调节是细胞和血管生物学研究中的一个新兴领域。我们提供的证据表明，过氧亚硝酸盐，强大的氧化和硝化自由基，是至关重要的参与VEGF信号的转导。我们测试的假设，VEGF诱导过氧亚硝酸盐的形成，导致酪氨酸磷酸化和介导的内皮细胞迁移和管的形成，通过研究血管内皮细胞在体外和缺氧诱导的新血管形成的模型在体内。特异性过氧亚硝酸盐分解催化剂FeTPPs阻断VEGF诱导的VEGFR 2和c-Src磷酸化，并抑制内皮细胞迁移和管形成。此外，外源性过氧亚硝酸盐模拟VEGF活性，引起VEGFR 2磷酸化，刺激体外内皮细胞生长和管形成以及体内新血管生长。选择性硝化抑制剂表儿茶素增强了VEGF在激活VEGFR 2、c-Src和促进内皮细胞生长、迁移和体外管形成以及体内视网膜新生血管形成中的血管生成功能。用FeTPP分解过氧亚硝酸盐或用巯基供体NAC阻断氧化在体外和体内阻断VEGF的血管生成功能。总之，过氧亚硝酸盐是至关重要的参与转导血管内皮生长因子的血管生成信号通过硝化独立和氧化介导的酪氨酸磷酸化。
The modulation of angiogenic signaling by reactive oxygen species (ROS) is an emerging area of interest in cellular and vascular biology research. We provide evidence here that peroxynitrite, the powerful oxidizing and nitrating free radical, is critically involved in transduction of the VEGF signal. We tested the hypothesis that VEGF induces peroxynitrite formation, which causes tyrosine phosphorylation and mediates endothelial cell migration and tube formation, by studies of vascular endothelial cells in vitro and in a model of hypoxia-induced neovascularization in vivo. The specific peroxynitrite decomposition catalyst FeTPPs blocked VEGF-induced phosphorylation of VEGFR2 and c-Src and inhibited endothelial cell migration and tube formation. Furthermore, exogenous peroxynitrite mimicked VEGF activity in causing phosphorylation of VEGFR2 and stimulating endothelial cell growth and tube formation in vitro and new blood vessel growth in vivo. The selective nitration inhibitor epicatechin enhanced VEGF's angiogenic function in activating VEGFR2, c-Src, and promoting endothelial cell growth, migration, and tube formation in vitro and retinal neovascularization in vivo. Decomposing peroxynitrite with FeTPPs or blocking oxidation using the thiol donor NAC blocked VEGF's angiogenic functions in vitro and in vivo. In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation.