HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin

Masanobu Morita, Osamu Ohneda, Toshiharu Yamashita, Satoru Takahashi, Norio Suzuki, Osamu Nakajima, Shimako Kawauchi, Masatsugu Ema, Shigeki Shibahara, Tetsuo Udono, Makoto Tamai, Kazuhiro Sogawa, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journalArticlepeer-review

160 Citations (Scopus)


An HLF (HIF-1α-like factor)/HIF-2α-knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice. To investigate the role of HLF in adult pathological angiogenesis, we generated HLF-knockdown (HLFkd/kd)mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLFkd/kdmice expressing 80-20% reduction, depending on the tissue, in wild-type HLF mRNA were fertile and apparently normal. Hyperoxia-normoxia treatment, used as a murine model of retinopathy of prematurity (ROP), induced neovascularization in wild-type mice, but not in HLFkd/dmice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLFkd/kdmice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLFkd/kdmice. Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was significantly affected, in parallel with HLF expression. Together with the results from intraperitoneal injection of Epo into HLFkd/kdmouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

Original languageEnglish
Pages (from-to)1134-1146
Number of pages13
JournalEMBO Journal
Issue number5
Publication statusPublished - 2003 Mar 3
Externally publishedYes


  • Erythropoietin
  • HLF
  • Neovascularization
  • Retinopathy
  • VEGF

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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