Caffeine promotes angiogenesis through modulating endothelial mitochondrial dynamics
Caffeine promotes angiogenesis through modulating endothelial mitochondrial dynamics
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咖啡因通过调节内皮线粒体动力学促进血管生成
DOI：
10.1038/s41401-021-00623-6
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发表时间：
2021-03
影响因子：
8.2
通讯作者：
Ning Tan
中科院分区：
文献类型：
--
作者：
Litao Wang;Pengcheng He;Anqi Li;Kaixiang Cao;Jingwei Yan;Shuai Guo;Lei Jiang;Lin Yao;Xiaoyan Dai;Du Feng;Yiming Xu;Ning Tan
咖啡因引起多种血管效应。在这项研究中，我们研究了生理浓度的咖啡因的血管生成作用，重点是血管生成过程中的内皮细胞行为（迁移和增殖）及其线粒体和生物能量机制。我们发现，咖啡因（10-50 μM）在体外显着增强血管生成，证明了浓度依赖性增加管形成，和迁移的人脐静脉内皮细胞（HUVEC），而不影响细胞增殖。咖啡因（50 μM）通过激活cAMP/PKA/AMPK信号通路促进内皮细胞迁移，cAMP类似物8-Br-cAMP可模拟该通路，PKA抑制剂H89、腺苷酸环化酶抑制剂SQ 22536或AMPK抑制剂化合物C可阻断该通路。此外，咖啡因（50 μM）通过增加HUVECs中线粒体分裂蛋白动力蛋白相关蛋白1（Drp 1）的磷酸化，从而增加其调节线粒体分裂的活性，从而诱导显著的线粒体缩短。通过Mdivi-1（10 μM）药理学阻断Drp 1或通过Drp 1沉默干扰线粒体分裂显著抑制咖啡因诱导的板状伪足形成和内皮细胞迁移。此外，我们发现，咖啡因诱导的线粒体分裂导致更多的线粒体在片状伪足区域的积累和线粒体能量的增强，这两者都是细胞迁移所必需的。在后肢缺血的小鼠模型中，给予咖啡因（每天200 mL饮用水中的0.05%，持续14天）显著促进缺血后肢中的血管生成和灌注以及内皮AMPK信号传导的激活。综上所述，咖啡因通过cAMP/PKA/AMPK信号通路诱导线粒体分裂。线粒体分裂是咖啡因诱导的内皮细胞迁移的一个完整过程，通过改变线粒体的分布和能量。
Caffeine induces multiple vascular effects. In this study we investigated the angiogenic effect of physiological concentrations of caffeine with focus on endothelial cell behaviors (migration and proliferation) during angiogenesis and its mitochondrial and bioenergetic mechanisms. We showed that caffeine (10–50 μM) significantly enhanced angiogenesis in vitro, evidenced by concentration-dependent increases in tube formation, and migration of human umbilical vein endothelial cells (HUVECs) without affecting cell proliferation. Caffeine (50 μM) enhanced endothelial migration via activation of cAMP/PKA/AMPK signaling pathway, which was mimicked by cAMP analog 8-Br-cAMP, and blocked by PKA inhibitor H89, adenylate cyclase inhibitor SQ22536 or AMPK inhibitor compound C. Furthermore, caffeine (50 μM) induced significant mitochondrial shortening through the increased phosphorylation of mitochondrial fission protein dynamin-related protein 1 (Drp1) in HUVECs, which increased its activity to regulate mitochondrial fission. Pharmacological blockade of Drp1 by Mdivi-1 (10 μM) or disturbance of mitochondrial fission by Drp1 silencing markedly suppressed caffeine-induced lamellipodia formation and endothelial cell migration. Moreover, we showed that caffeine-induced mitochondrial fission led to accumulation of more mitochondria in lamellipodia regions and augmentation of mitochondrial energetics, both of which were necessary for cell migration. In a mouse model of hindlimb ischemia, administration of caffeine (0.05% in 200 mL drinking water daily, for 14 days) significantly promoted angiogenesis and perfusion as well as activation of endothelial AMPK signaling in the ischemic hindlimb. Taken together, caffeine induces mitochondrial fission through cAMP/PKA/AMPK signaling pathway. Mitochondrial fission is an integral process in caffeine-induced endothelial cell migration by altering mitochondrial distribution and energetics.
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影响因子：
29
作者：
Sawada N;Jiang A;Takizawa F;Safdar A;Manika A;Tesmenitsky Y;Kang KT;Bischoff J;Kalwa H;Sartoretto JL;Kamei Y;Benjamin LE;Watada H;Ogawa Y;Higashikuni Y;Kessinger CW;Jaffer FA;Michel T;Sata M;Croce K;Tanaka R;Arany Z
通讯作者：
Arany Z
影响因子：
1.3
作者：
Echeverri D;Montes FR;Cabrera M;Galán A;Prieto A
通讯作者：
Prieto A
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
影响因子：
11.1
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
通讯作者：
Huo Y
DOI：
10.1038/nrm3176
发表时间：
2011-08-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter