The coordination of metabolic signals among different cellular components in pathological retinal angiogenesis is poorly understood. Here, we showed that in the pathological angiogenic vascular niche, retinal myeloid cells, particularly macrophages/microglia that are spatially adjacent to endothelial cells (ECs), are highly glycolytic. We refer to these macrophages/microglia that exhibit a unique angiogenic phenotype with increased expression of both M1 and M2 markers and enhanced production of both proinflammatory and proangiogenic cytokines as pathological retinal angiogenesis–associated glycolytic macrophages/microglia (PRAGMs). The phenotype of PRAGMs was recapitulated in bone marrow–derived macrophages or retinal microglia stimulated by lactate that was produced by hypoxic retinal ECs. Knockout of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3; Pfkfb3 for rodents), a glycolytic activator in myeloid cells, impaired the ability of macrophages/microglia to acquire an angiogenic phenotype, rendering them unable to promote EC proliferation and sprouting and pathological neovascularization in a mouse model of oxygen-induced proliferative retinopathy. Mechanistically, hyperglycolytic macrophages/microglia produced large amount of acetyl–coenzyme A, leading to histone acetylation and PRAGM-related gene induction, thus reprogramming macrophages/microglia into an angiogenic phenotype. These findings reveal a critical role of glycolytic metabolites as initiators of reciprocal activation of macrophages/microglia and ECs in the retinal angiogenic niche and suggest that strategies targeting the metabolic communication between these cell types may be efficacious in the treatment of pathological retinal angiogenesis.

对病理性视网膜血管生成中不同细胞成分之间代谢信号的协调知之甚少。在这里，我们发现在病理性血管生成血管壁龛中，视网膜髓细胞，特别是与内皮细胞 (EC) 空间相邻的巨噬细胞/小胶质细胞，具有高度糖酵解。我们将这些表现出独特血管生成表型的巨噬细胞/小胶质细胞称为 M1 和 M2 标志物的表达增加和促炎和促血管生成细胞因子的增加，称为病理性视网膜血管生成相关糖酵解巨噬细胞/小胶质细胞 (PRAGM)。PRAGMs 的表型在骨髓来源的巨噬细胞或视网膜小胶质细胞中被概括，由低氧视网膜 ECs 产生的乳酸刺激。敲除 6-phosphofructo-2-kinase/fructose-2，PFKFB3 ; Pfkfb3对于啮齿类动物），骨髓细胞中的糖酵解激活剂，损害巨噬细胞/小胶质细胞获得血管生成表型的能力，使它们无法在氧诱导的增殖性视网膜病变小鼠模型中促进 EC 增殖和发芽和病理性新血管形成。从机制上讲，高糖酵解巨噬细胞/小胶质细胞产生大量乙酰辅酶 A，导致组蛋白乙酰化和 PRAGM 相关基因诱导，从而将巨噬细胞/小胶质细胞重编程为血管生成表型。