Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis.
Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis.
复制标题
细胞内腺苷调节内皮细胞的表观遗传编程以促进血管生成
DOI：
10.15252/emmm.201607066
复制
发表时间：
2017-09
影响因子：
11.1
通讯作者：
Huo Y
中科院分区：
文献类型：
--
作者：
Xu Y;Wang Y;Yan S;Zhou Y;Yang Q;Pan Y;Zeng X;An X;Liu Z;Wang L;Xu J;Cao Y;Fulton DJ;Weintraub NL;Bagi Z;Hoda MN;Wang X;Li Q;Hong M;Jiang X;Boison D;Weber C;Wu C;Huo Y
核苷腺苷是一种强大的血管内稳态调节剂，但目前尚不清楚腺苷代谢酶腺苷激酶(ADK)的表达或功能以及细胞内的腺苷水平如何影响血管生成。我们在这里表明，缺氧降低了人内皮细胞ADK的表达，增加了细胞内腺苷的水平。ADK基因敲除(KD)增加了细胞内的腺苷，促进了人内皮细胞的增殖、迁移和血管新生萌发。此外，内皮ADK缺乏的小鼠表现出血管生成增加，表现为视网膜和后脑血管的快速发展，皮肤伤口的愈合加快，以及缺血后肢动脉血流的迅速恢复。在机制上，一系列促血管生成基因的启动子在ADK KD细胞中发生了低甲基化，尤其是VEGFR2。甲基化特异性聚合酶链式反应、亚硫酸氢盐测序和甲基化DNA免疫沉淀进一步证实在ADK缺乏的内皮细胞中VEGFR2启动子区域存在低甲基化。因此，ADK的缺失或失活会增加血管内皮细胞中VEGFR2的表达和信号。基于这些发现，我们认为在低氧环境下ADK下调诱导内皮细胞内腺苷水平升高是促进血管生成的重要内在机制之一。
The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine‐metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced by the rapid development of the retinal and hindbrain vasculature, increased healing of skin wounds, and prompt recovery of arterial blood flow in the ischemic hindlimb. Mechanistically, hypomethylation of the promoters of a series of pro‐angiogenic genes, especially for VEGFR2 in ADK KD cells, was demonstrated by the Infinium methylation assay. Methylation‐specific PCR, bisulfite sequencing, and methylated DNA immunoprecipitation further confirmed hypomethylation in the promoter region of VEGFR2 in ADK‐deficient endothelial cells. Accordingly, loss or inactivation of ADK increased VEGFR2 expression and signaling in endothelial cells. Based on these findings, we propose that ADK downregulation‐induced elevation of intracellular adenosine levels in endothelial cells in the setting of hypoxia is one of the crucial intrinsic mechanisms that promote angiogenesis.