Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice

J Clin Invest. 2008 Jul;118(7):2393-403. doi: 10.1172/JCI34882.


To meet tissue requirements for oxygen, capillaries must be properly distributed without excess or shortage. In this process, tissue oxygen concentration is well known to determine capillary density via the hypoxia-induced cascade, in which HIFs and VEGF play key roles. However, some additional mechanisms modulating this cascade are suggested to be involved in precise capillary network formation. Here, we showed that leukemia inhibitory factor (LIF) was predominantly expressed in developing endothelium, while its receptor was expressed in surrounding cells such as retinal astrocytes. The retinas of Lif(-/-) mice displayed increased microvessel density accompanied by sustained tip cell activity, due to increased VEGF expression by astrocytes in the vascularized area. Lif(-/-) mice resisted hyperoxygen insult in the oxygen-induced retinopathy model, whereas they paradoxically had increased numbers of neovascular tufts. In an in vitro study, LIF inhibited hypoxia-induced VEGF expression and proliferation in cultured astrocytes. Lif(-/-) mice also exhibited similarly increased microvessel density and upregulated VEGF in various tissues outside the retina. Together, these findings suggest that tissues and advancing vasculature communicate to ensure adequate vascularization using LIF as well as oxygen, which suggests a new strategy for antiangiogenic therapy in human diseases such as diabetic retinopathy and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Gene Expression / drug effects
  • Glial Fibrillary Acidic Protein
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Janus Kinase 2 / antagonists & inhibitors
  • Leukemia Inhibitory Factor / genetics
  • Leukemia Inhibitory Factor / pharmacology
  • Leukemia Inhibitory Factor / physiology*
  • Leukemia Inhibitory Factor Receptor alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Nerve Tissue Proteins / metabolism
  • Oxygen / pharmacology
  • Oxygen / physiology*
  • Retina / cytology
  • Retina / drug effects
  • Retina / metabolism
  • STAT3 Transcription Factor / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Glial Fibrillary Acidic Protein
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Leukemia Inhibitory Factor
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Lif protein, mouse
  • Lifr protein, mouse
  • Nerve Tissue Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Vascular Endothelial Growth Factor A
  • glial fibrillary astrocytic protein, mouse
  • vascular endothelial growth factor A, mouse
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Oxygen