The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner

Ayako Nakamura-Ishizu, Toshihide Kurihara, Yuji Okuno, Yoko Ozawa, Kazuo Kishi, Nobuhito Goda, Kazuo Tsubota, Hideyuki Okano, Toshio Suda, Yoshiaki Kubota

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)


The vascular and nervous systems display a high degree of cross-talk and depend on each other functionally. In the vascularization of the central nervous system, astrocytes have been thought to sense tissue oxygen levels in hypoxia-inducible factors (HIFs)-dependent manner and control the vascular growth into the hypoxic area by secreting VEGF. However, recent genetic evidences demonstrate that not only astrocyte HIFs but also astrocyte VEGF expression is dispensable for developmental angiogenesis of the retina. This study demonstrates that hypoxia-inducible factor 1 alpha subunit (HIF-1α), a key transcription factor involved in cellular responses to hypoxia, is most abundantly expressed in the neuroretina, especially retinal progenitor cells (RPCs). A neuroretina-specific knockout of HIF-1α (αCre+Hif1α flox/flox) showed impaired vascular development characterized by decreased tip cell filopodia and reduced vessel branching. The astrocyte network was hypoplastic in αCre+Hif1α flox/flox mice. Mechanistically, platelet-derived growth factor A (PDGF-A), a mitogen for astrocytes, was downregulated in the neuroretina of αCre+Hif1α flox/flox mice. Supplementing PDGF-A restored reduced astrocytic and vascular density in αCre+Hif1α flox/flox mice. Our data demonstrates that the neuroretina but not astrocytes acts as a primary oxygen sensor which ultimately controls the retinal vascular development by regulating an angiogenic astrocyte template.

Original languageEnglish
Pages (from-to)106-114
Number of pages9
JournalDevelopmental Biology
Issue number1
Publication statusPublished - 01-03-2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


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