Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis

Zhiping Liu,Neal L Weintraub,Ruth B Caldwell,Sarah Lu,Xizhen Xu,Ismail Kaddour‐Djebbar ,Chaodong Wu,Xiao Ling Liu ,Yiming Xu,Shuya Zhang,Lois E H Smith ,Akrit Sodhi,Mei Hong,Qinkai Li,David Fulton ,Aftab Ahmad,Siyuan Yan,Jiaojiao Wang,Yong Wang,Jiang‐Fan Chen ,Yuwen Zhou ,Xuejun Jiang,Qiuhua Yang,Ye Sun,Zhongjie Fu,Mohamed Al‐Shabrawey ,Wenbo Zhang,Xiangwu Zeng ,Xuejiao Gu,Yuqing Huo

doi:10.1038/s41467-017-00551-2

Abstract

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.

Highlights

Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies
Real-time PCR analysis revealed that expression of the Adora2a gene was significantly increased while adenosine A1 receptor (Adora1) and adenosine A2B receptor (Adora2b) levels were reduced on postnatal day (P)[17] in oxygen-induced retinopathy (OIR) retinas, compared with controls in room air (RA) (Fig. 1b)
We found no noticeable changes in the expression of Adors from P7 to P12 (Fig. 1c), whereas expression of Adora2a steadily increased from P12 to P17 (Fig. 1d), indicative of a sustained increase in the expression of Adora2a throughout the hypoxic-ischemic phase of OIR

Summary

Introduction

Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. 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. Increased glycolysis, evidenced by an increased level of lactate in vitreous fluid, has been demonstrated in patients with PDR11 Due to this close association between EC glycolysis and pathological retinal angiogenesis as well as substantial demand for new treatment of retinopathies, it is pressing to uncover practical targeting molecules that regulate the glycolytic pathway in retinal ECs. Hyperactivation of adenosine signaling has been implicated in cellular responses to hypoxia and the development of various ischemic diseases[12]. Our study further demonstrated that endotheliumspecific Adora2a deletion reduces glycolysis and pathological neovascularization in retinopathy in vivo

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Results

Conclusion