Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Nat Commun. 2017 Sep 19;8(1):584. doi: 10.1038/s41467-017-00551-2.
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-specific Adora2a deletion 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.Pathological angiogenesis in the retina is a major cause of blindness. Here the authors show that adenosine receptor A2A drives pathological angiogenesis in the oxygen-induced retinopathy mouse model by promoting glycolysis in endothelial cells via the ERK/Akt/HIF-1α pathway, thereby suggesting new therapeutic targets for disease treatment.
腺苷/腺苷受体介导的信号转导与各种缺血性疾病的发生有关，包括缺血性视网膜病变。在这里，我们发现腺苷 A2a 受体（ADORA2A）促进了缺氧诱导因子-1（HIF-1）依赖性内皮细胞糖酵解，这对于增生性视网膜病变中的病理性血管生成至关重要。在氧诱导的视网膜病变（OIR）小鼠的视网膜中，ADORA2A 的表达显著增加。内皮细胞特异性而非巨噬细胞特异性的 Adora2a 缺失会降低关键的糖酵解酶，并减少 OIR 小鼠中的病理性新生血管形成。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 敲低会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、出芽和小管形成。在机制上，ADORA2A 的激活通过 ERK 和 Akt 依赖性 HIF-1α 蛋白的翻译激活促进糖酵解酶的转录诱导。总之，这些发现推动了 ADORA2A 作为治疗增生性视网膜病变和其他依赖病理性血管生成的疾病的治疗靶点的转化。
