Leukemia inhibitory factor regulates microvessel density by modulating oxygen-3 dependent VEGF expression in mice

Yoshiaki Kubota, Masanori Hirashima, Kazuo Kishi, Colin L. Stewart, Toshio Suda

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2393-2403
Number of pages11
JournalJournal of Clinical Investigation
Issue number7
Publication statusPublished - 2008 Jul 1

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Leukemia inhibitory factor regulates microvessel density by modulating oxygen-3 dependent VEGF expression in mice'. Together they form a unique fingerprint.

Cite this