Oral Biochemistry and Molecular Biology, Department of Oral Health Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-ku, Sapporo, 060-8586, Japan.
Oral Biochemistry and Molecular Biology, Department of Oral Health Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-ku, Sapporo, 060-8586, Japan.
Biochem Biophys Res Commun. 2020 Aug 27;529(3):596-602. doi: 10.1016/j.bbrc.2020.06.085. Epub 2020 Jul 17.
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-mCherry) 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.
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作用。低剂量的甘氨酸促进血管生成，而高剂量则导致抗血管生成。磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路参与生理发育和病理性事件（包括肿瘤和炎症）的血管生成。我们使用表达在血管内皮细胞中的荧光蛋白的转基因斑马鱼 Tg(fli1a:Myr-mCherry)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。mTORC1（雷帕霉素和依维莫司）、mTORC1/mTORC2（KU0063794）、PI3K（LY29400）和 Akt（Akt 抑制剂）抑制剂处理会降低节间血管（ISVs）的发育。这些抑制剂取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产生抗血管生成作用。mTOR 信号通路调节血管内皮生长因子（VEGF）和一氧化氮（NO）合酶（NOS）的基因表达，VEGF 是主要的血管生成因子，NOS 是血管生成介质 NO 的合成酶。VEGF 和 NOS 的表达与甘氨酸和 mTOR 抑制剂诱导的血管特征一致。我们的结果表明，PI3K/Akt/mTOR 信号通路可能与外源性甘氨酸对体内血管生成的浓度依赖性双相作用相互作用。mTOR 信号通路是癌症治疗的关键靶点，因此，将 mTOR 抑制剂与甘氨酸结合可能是控制血管生成的一种潜在方法。
