Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis.
Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis.
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内皮腺苷 A2a 受体介导的糖酵解对于病理性视网膜血管生成至关重要
DOI：
10.1038/s41467-017-00551-2
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发表时间：
2017-09-19
影响因子：
16.6
通讯作者：
Huo Y
中科院分区：
文献类型：
--
作者：
Liu Z;Yan S;Wang J;Xu Y;Wang Y;Zhang S;Xu X;Yang Q;Zeng X;Zhou Y;Gu X;Lu S;Fu Z;Fulton DJ;Weintraub NL;Caldwell RB;Zhang W;Wu C;Liu XL;Chen JF;Ahmad A;Kaddour-Djebbar I;Al-Shabrawey M;Li Q;Jiang X;Sun Y;Sodhi A;Smith L;Hong M;Huo Y
腺苷/腺苷受体介导的信号传导与多种缺血性疾病的发展有关，包括缺血性视网膜病。在这里，我们发现腺苷 A2a 受体 (ADORA2A) 促进缺氧诱导转录因子 1 (HIF-1) 依赖性内皮细胞糖酵解，这对于增殖性视网膜病的病理性血管生成至关重要。氧诱导性视网膜病变 (OIR) 小鼠的视网膜中 Adora2a 表达显着增加。内皮细胞特异性而非巨噬细胞特异性的 Adora2 缺失会降低 OIR 小鼠中关键的糖酵解酶并减少病理性新血管形成。在人原代视网膜微血管内皮细胞中，缺氧通过激活HIF-2α诱导ADORA2A的表达。 ADORA2A 敲低可降低缺氧诱导的糖酵解酶表达、糖酵解通量以及内皮细胞增殖、出芽和肾小管形成。从机制上讲，ADORA2A 激活通过 HIF-1α 蛋白的 ERK 和 Akt 依赖性翻译激活促进糖酵解酶的转录诱导。总而言之，这些发现促进了 ADORA2A 作为治疗增殖性视网膜病和其他依赖于病理性血管生成的疾病的治疗靶点的转化。
Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specificAdora2adeletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice. In human primary retinal microvascular endothelial cells, hypoxia induces the expression of ADORA2A by activating HIF-2α. ADORA2A knockdown decreases hypoxia-induced glycolytic enzyme expression, glycolytic flux, and endothelial cell proliferation, sprouting and tubule formation. Mechanistically, ADORA2A activation promotes the transcriptional induction of glycolytic enzymes via ERK- and Akt-dependent translational activation of HIF-1α protein. Taken together, these findings advance translation of ADORA2A as a therapeutic target in the treatment of proliferative retinopathies and other diseases dependent on pathological angiogenesis.
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影响因子：
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