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Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8
Angiogenesis ( IF 9.8 ) Pub Date : 2021-03-02 , DOI: 10.1007/s10456-021-09772-y
Vivien Becker 1 , Xin Hui 2 , Lisa Nalbach 1 , Emmanuel Ampofo 1 , Peter Lipp 2 , Michael D Menger 1 , Matthias W Laschke 1 , Yuan Gu 1
Affiliation  

Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3R)-(−)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cytotoxic doses of linalool significantly inhibited HDMEC proliferation, migration, tube formation and spheroid sprouting. Linalool also suppressed the vascular sprouting from rat aortic rings. In addition, Matrigel plugs containing linalool exhibited a significantly reduced microvessel density 7 days after implantation into BALB/c mice. Mechanistic analyses revealed that linalool promotes the phosphorylation of extracellular signal-regulated kinase (ERK), downregulates the intracellular level of adenosine triphosphate (ATP) and activates the transient receptor potential cation channel subfamily M (melastatin) member (TRPM)8 in HDMECs. Inhibition of ERK signaling, supplementation of ATP and blockade of TRPM8 significantly counteracted linalool-suppressed HDMEC spheroid sprouting. Moreover, ATP supplementation completely reversed linalool-induced ERK phosphorylation. In addition, linalool-induced ERK phosphorylation inhibited the expression of bone morphogenetic protein (BMP)-2 and linalool-induced TRPM8 activation caused the inhibition of β1 integrin/focal adhesion kinase (FAK) signaling. These findings indicate an anti-angiogenic effect of linalool, which is mediated by downregulating intracellular ATP levels and activating TRPM8.



中文翻译:

芳樟醇通过下调细胞内 ATP 水平和激活 TRPM8 抑制内皮细胞的血管生成活性

血管生成对各种疾病至关重要,例如癌症和糖尿病视网膜病变。因此,抗血管生成疗法被认为是对抗这些疾病的有力策略。先前的研究报道,无环单萜芳樟醇具有抗癌、抗炎和抗氧化活性。然而,芳樟醇对血管生成的影响仍然难以捉摸。因此,我们研究了(3 R)-(-)-芳樟醇,芳樟醇的主要对映异构体,通过一组血管生成测定对人真皮微血管内皮细胞 (HDMEC) 的血管生成活性进行了研究。芳樟醇的非细胞毒性剂量显着抑制 HDMEC 增殖、迁移、管形成和球状体发芽。芳樟醇还抑制大鼠主动脉环的血管发芽。此外,含有芳樟醇的基质胶塞在植入 BALB/c 小鼠后 7 天表现出显着降低的微血管密度。机理分析表明,芳樟醇促进细胞外信号调节激酶 (ERK) 的磷酸化,下调三磷酸腺苷 (ATP) 的细胞内水平,并激活 HDMECs 中的瞬时受体电位阳离子通道亚家族 M (melastatin) 成员 (TRPM)8。抑制 ERK 信号,补充 ATP 和阻断 TRPM8 显着抵消了芳樟醇抑制的 HDMEC 球体发芽。此外,补充 ATP 完全逆转了芳樟醇诱导的 ERK 磷酸化。此外,芳樟醇诱导的 ERK 磷酸化抑制骨形态发生蛋白 (BMP)-2 的表达,芳樟醇诱导的 TRPM8 活化导致 β1 整合素/粘着斑激酶 (FAK) 信号传导的抑制。这些发现表明芳樟醇具有抗血管生成作用,其通过下调细胞内 ATP 水平和激活 TRPM8 介导。芳樟醇诱导的 ERK 磷酸化抑制骨形态发生蛋白 (BMP)-2 的表达,芳樟醇诱导的 TRPM8 活化导致 β1 整合素/粘着斑激酶 (FAK) 信号传导的抑制。这些发现表明芳樟醇具有抗血管生成作用,其通过下调细胞内 ATP 水平和激活 TRPM8 介导。芳樟醇诱导的 ERK 磷酸化抑制骨形态发生蛋白 (BMP)-2 的表达,芳樟醇诱导的 TRPM8 活化导致 β1 整合素/粘着斑激酶 (FAK) 信号传导的抑制。这些发现表明芳樟醇具有抗血管生成作用,其通过下调细胞内 ATP 水平和激活 TRPM8 介导。

更新日期:2021-03-02
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