PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells.
PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells.
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PI3K、Rho 和 ROCK 在缺氧诱导的肺动脉血管内皮细胞 ATP 释放和 ATP 刺激的血管生成反应中发挥关键作用。
DOI：
10.1152/ajplung.00038.2009
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Gerasimovskaya,EvgeniaV
中科院分区：
文献类型：
--
作者：
Woodward,HeatherN;Anwar,Adil;Riddle,Suzette;Taraseviciene-Stewart,Laimute;Fragoso,Miguel;Stenmark,KurtR;Gerasimovskaya,EvgeniaV
我们最近报道，长期缺氧动物的肺动脉（PA）外膜发生血管滋养管扩张，并且细胞外ATP是分离的血管滋养管内皮细胞（VVEC）的促血管生成因子。然而，PA 血管壁中细胞外 ATP 的来源及其释放的分子机制仍然难以捉摸。研究人员进行了研究来探索 VVEC 是否会因缺氧而释放 ATP，并确定参与该过程的信号通路。我们发现缺氧（1-3% O2）会导致 VVEC 中时间和 O2 依赖性的 ATP 释放。与囊泡转运抑制剂（莫能菌素、布雷菲德菌素 A 和 N-乙基马来酰亚胺）预孵育显着降低了 VVEC 条件培养基中 ATP 的积累，表明缺氧诱导的 ATP 释放是通过囊泡胞吐作用发生的。此外，缺氧和外源添加 ATP 都会导致 PI3K 的激活和 GTP 结合的 RhoA 以时间依赖性方式积累。通过小干扰 RNA 对 PI3K 和 ROCK 进行药理学抑制或敲除 RhoA，可显着消除缺氧诱导的 VVEC ATP 释放。此外，RhoA 和 ROCK 在 ATP 诱导的 VVEC DNA 合成、迁移和管形成增加中发挥关键作用，表明 PI3K、Rho 和 ROCK 对 ATP 释放的自分泌机制和 ATP 介导的 VVEC 血管生成激活都有功能贡献。总而言之，我们的研究结果为将缺氧诱导的细胞外 ATP 增加和血管滋养管扩张联系起来的信号传导机制提供了新的证据。
We recently reported that vasa vasorum expansion occurs in the pulmonary artery (PA) adventitia of chronically hypoxic animals and that extracellular ATP is a pro-angiogenic factor for isolated vasa vasorum endothelial cells (VVEC). However, the sources of extracellular ATP in the PA vascular wall, as well as the molecular mechanisms underlying its release, remain elusive. Studies were undertaken to explore whether VVEC release ATP in response to hypoxia and to determine signaling pathways involved in this process. We found that hypoxia (1–3% O2) resulted in time- and O2-dependent ATP release from VVEC. Preincubation with the inhibitors of vesicular transport (monensin, brefeldin A, andN-ethylmaleimide) significantly decreased ATP accumulation in the VVEC conditioned media, suggesting that hypoxia-induced ATP release occurs through vesicular exocytosis. Additionally, both hypoxia and exogenously added ATP resulted in the activation of PI3K and accumulation of GTP-bound RhoA in a time-dependent manner. Pharmacological inhibition of PI3K and ROCK or knockout of RhoA by small interfering RNA significantly abolished hypoxia-induced ATP release from VVEC. Moreover, RhoA and ROCK play a critical role in ATP-induced increases in VVEC DNA synthesis, migration, and tube formation, indicating a functional contribution of PI3K, Rho, and ROCK to both the autocrine mechanism of ATP release and ATP-mediated angiogenic activation of VVEC. Taken together, our findings provide novel evidence for the signaling mechanisms that link hypoxia-induced increases in extracellular ATP and vasa vasorum expansion.
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