Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase
Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase
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DOI：
10.1152/ajpheart.01081.2005
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发表时间：
2006-10-01
影响因子：
4.8
通讯作者：
Meyrick, Barbara
中科院分区：
文献类型：
--
作者：
Chen, Jian-Xiong;Zeng, Heng;Meyrick, Barbara
血管生成素-1诱导的血管生成受内皮NADPH氧化酶调节。美国生理学杂志心脏循环生理学291：H1563-H1572，2006年。首次发表于2006年5月5日; doi：10.1152/ajpheart.01081.2005。活性氧（reactive oxygen species，ROS）在动脉粥样硬化、高血压等多种心血管疾病的发病机制中起着重要作用。内皮细胞NADPH氧化酶是细胞内ROS的主要来源。本研究探讨内皮细胞NADPH氧化酶衍生的活性氧在血管生成素-1（Ang-1）诱导的血管生成中的作用。将猪冠状动脉内皮细胞（PCAECs）暴露于Ang-1（250 ng/ml）长达30 min，导致细胞内ROS一过性和剂量依赖性增加。用NADPH氧化酶抑制剂二亚苯基碘鎓（DPI，10 μ M）和夹竹桃素（200 μ M）预处理30分钟，抑制Ang-1刺激的ROS。DPI或夹竹桃素预处理也显著减弱Ang-1诱导的Akt和p44/42 MAPK磷酸化。此外，抑制NADPH氧化酶显着抑制Ang-1诱导的内皮细胞迁移和从内皮球体发芽。使用来自野生型（WT）小鼠和NADPH氧化酶p47（phox）组分（p47（phox-/-））缺陷小鼠的小鼠心脏微血管内皮细胞，我们发现，尽管Ang-1刺激WT细胞中的细胞内ROS、Akt和p42/44 MAPK磷酸化以及细胞迁移，但这些反应在来自p47（phox-/-）小鼠的细胞中受到显著抑制。此外，来自p47（phox-/-）小鼠的主动脉环暴露于Ang-1显示出比WT小鼠更少的血管出芽。Tie-2受体的抑制抑制Ang-1诱导的内皮迁移和血管发芽。总之，我们的数据有力地表明，内皮NADPH氧化酶衍生的ROS在Ang-1诱导的血管生成中起着关键作用。
Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. Am J Physiol Heart Circ Physiol 291: H1563-H1572, 2006. First published May 5, 2006; doi:10.1152/ajpheart.01081.2005.-Reactive oxygen species (ROS) play a central role in the pathogenesis of many cardiovascular diseases, such as atherosclerosis and hypertension. Endothelial NADPH oxidase is the major source of intracellular ROS. The present study investigated the role of endothelial NADPH oxidase-derived ROS in angiopoietin-1 (Ang-1)-induced angiogenesis. Exposure of porcine coronary artery endothelial cells (PCAECs) to Ang-1 (250 ng/ml) for periods up to 30 min led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes of pretreatment with the NADPH oxidase inhibitors diphenylene iodinium (DPI, 10 mu M) and apocynin (200 mu M) suppressed Ang-1-stimulated ROS. Pretreatment with either DPI or apocynin also significantly attenuated Ang-1-induced Akt and p44/42 MAPK phosphorylation. In addition, inhibition of NADPH oxidase significantly suppressed Ang-1-induced endothelial cell migration and sprouting from endothelial spheroids. Using mouse heart microvascular endothelial cells from wild-type (WT) mice and mice deficient in the p47(phox) component of NADPH oxidase (p47(phox-/-)), we found that although Ang-1 stimulated intracellular ROS, Akt and p42/44 MAPK phosphorylation, and cell migration in WT cells, the responses were strikingly suppressed in cells from the p47(phox-/-) mice. Furthermore, exposure of aortic rings from p47(phox-/-) mice to Ang-1 demonstrated fewer vessel sprouts than WT mice. Inhibition of the Tie-2 receptor inhibited Ang-1-induced endothelial migration and vessel sprouting. Together, our data strongly suggest that endothelial NADPH oxidase-derived ROS play a critical role in Ang-1-induced angiogenesis.