The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development
The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development
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DOI：
10.1016/j.bbrc.2020.06.085
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发表时间：
2020-08-27
影响因子：
3.1
通讯作者：
Tamura, Masato
中科院分区：
文献类型：
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作者：
Tsuji-Tamura, Kiyomi;Sato, Mari;Tamura, Masato
甘氨酸是一种非必需氨基酸，对血管生成具有浓度依赖性的双相效应。低剂量的甘氨酸促进血管生成，而高剂量的甘氨酸则会抑制血管生成。磷脂酰肌醇3-激酶(PI3K)/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路参与血管生成的生理发育和病理事件，包括肿瘤和炎症。我们利用在血管内皮细胞中表达荧光蛋白的转基因斑马鱼Tg(fli1a:Myr-mCherty)（ncv1）胚胎，评估了PI3K/Akt/mTOR信号通路在血管发育中的作用以及与甘氨酸的相互作用。使用mTORC1（雷帕霉素和依维莫司）、mTORC1/mTORC2 （KU0063794）、PI3K （LY29400）和Akt （Akt抑制剂）抑制剂治疗可减少节段间血管（isv）的发展。这些抑制剂抵消了低剂量甘氨酸的血管生成作用，而与高剂量甘氨酸协同作用，抗血管生成。mTOR信号通路调节血管内皮生长因子（VEGF）和一氧化氮合成酶（NOS）的基因表达，VEGF是一种主要的血管生成因子，NOS是一种合成血管生成介质NO的酶。VEGF和NOS的表达与甘氨酸和mTOR抑制剂诱导的血管特征一致。我们的研究结果表明，PI3K/Akt/mTOR信号可能与外源性甘氨酸对体内血管生成的剂量依赖性双相作用相互作用。mTOR信号是癌症治疗的关键靶点，因此，mTOR抑制剂与甘氨酸联合使用可能是控制血管生成的潜在方法。(C) 2020爱思唯尔公司版权所有。
Glycine, a non-essential amino acid, exerts concentration-dependent biphasic effects on angiogenesis. Low-doses of glycine promote angiogenesis, whereas high-doses cause anti-angiogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling participates in angiogenesis of both physiological development, and pathological events including tumor and inflammation. We assessed the role of PI3K/Akt/mTOR signaling in vascular development, and the interaction with glycine, using transgenic zebrafish Tg(fli1a:Myr-mCherty)(ncv1) embryos expressing fluorescent proteins in vascular endothelial cells. Treatment with inhibitors of mTORC1 (rapamycin and everolimus), mTORC1/mTORC2 (KU0063794), PI3K (LY29400), and Akt (Akt inhibitor) decreased the development of intersegmental vessels (ISVs). These inhibitors cancelled the angiogenic effects of a low-dose of glycine, while acted synergistically with a high-dose of glycine in anti-angiogenesis. mTOR signaling regulates the gene expression of vascular endothelial growth factor (VEGF), a major angiogenic factor, and nitric oxide (NO) synthase (NOS), an enzyme for the synthesis of an angiogenic mediator NO. Expressions of VEGF and NOS were consistent with the vascular features induced by glycine and an mTOR inhibitor. Our results suggest that PI3K/Akt/mTOR signaling may interact with dose-dependent biphasic effects of exogenous glycine on in vivo angiogenesis. mTOR signaling is a key target for cancer therapy, thus, the combining mTOR inhibitors with glycine may be a potential approach for controlling angiogenesis. (C) 2020 Elsevier Inc. All rights reserved.