Extracellular Lactate Dehydrogenase A Release From Damaged Neurons Drives Central Nervous System Angiogenesis

EBioMedicine. 2018 Jan;27:71-85. doi: 10.1016/j.ebiom.2017.10.033. Epub 2017 Dec 7.

Abstract

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.

Keywords: Cancer; Cell proliferation; Inflammation; Multiple sclerosis.

MeSH terms

  • Animals
  • Axons / pathology
  • Cell Membrane / metabolism
  • Cell Proliferation
  • Central Nervous System / blood supply*
  • Central Nervous System / pathology*
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / enzymology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Endothelial Cells / enzymology
  • Extracellular Space / enzymology*
  • Glioblastoma / pathology
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / metabolism*
  • Lactate Dehydrogenase 5
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / enzymology*
  • Nerve Degeneration / pathology
  • Nerve Regeneration
  • Neurons / enzymology*
  • Neurons / pathology*
  • Protein Binding
  • Survival Analysis
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vimentin / metabolism

Substances

  • Isoenzymes
  • Vimentin
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • Vascular Endothelial Growth Factor Receptor-2