Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
EBioMedicine. 2018 Jan;27:71-85. doi: 10.1016/j.ebiom.2017.10.033. Epub 2017 Dec 7.
Angiogenesis, a prominent feature of pathology, is known to be guided by factors secreted by living cells around a lesion. Although many cells are disrupted in a response to injury, the relevance of degenerating cells in pathological angiogenesis is unclear. Here, we show that the release of lactate dehydrogenase A (LDHA) from degenerating neurons drives central nervous system (CNS) angiogenesis. Silencing neuronal LDHA expression suppressed angiogenesis around experimental autoimmune encephalomyelitis (EAE)- and controlled cortical impact-induced lesions. Extracellular LDHA-mediated angiogenesis was dependent on surface vimentin expression and vascular endothelial growth factor receptor (VEGFR) phosphorylation in vascular endothelial cells. Silencing vimentin expression in vascular endothelial cells prevented angiogenesis around EAE lesions and improved survival in a mouse model of glioblastoma. These results elucidate novel mechanisms that may mediate pathologic angiogenesis and identify a potential molecular target for the treatment of CNS diseases involving angiogenesis.
血管生成是病理学的一个显著特征，已知其受到病变周围分泌的活细胞因子的引导。尽管许多细胞在受伤时被破坏，但退化细胞在病理性血管生成中的相关性尚不清楚。在这里，我们表明，退化神经元释放的乳酸脱氢酶 A (LDHA) 驱动中枢神经系统 (CNS) 血管生成。沉默神经元 LDHA 表达可抑制实验性自身免疫性脑脊髓炎 (EAE) 和皮质控制冲击诱导损伤周围的血管生成。细胞外 LDHA 介导的血管生成依赖于血管内皮细胞表面波形蛋白的表达和血管内皮生长因子受体 (VEGFR) 的磷酸化。沉默血管内皮细胞中的波形蛋白表达可防止 EAE 病变周围的血管生成，并改善胶质母细胞瘤小鼠模型的存活率。这些结果阐明了可能介导病理性血管生成的新机制，并确定了治疗涉及血管生成的 CNS 疾病的潜在分子靶点。
