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 journalArticle

    40 Citations (Scopus)

    Abstract

    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
    Volume363
    Issue number1
    DOIs
    Publication statusPublished - 2012 Mar 1

    Fingerprint

    Hypoxia-Inducible Factor 1
    Astrocytes
    Blood Vessels
    Vascular Endothelial Growth Factor A
    Alpha Subunit Hypoxia-Inducible Factor 1
    Oxygen
    Retinal Vessels
    Pseudopodia
    Mitogens
    Nervous System
    Retina
    Transcription Factors
    Stem Cells
    Down-Regulation
    Central Nervous System
    Growth

    Keywords

    • Astrocyte
    • HIF-1α
    • Neuroretina
    • Retinal angiogenesis
    • Retinal progenitor cell

    ASJC Scopus subject areas

    • Developmental Biology
    • Cell Biology
    • Molecular Biology

    Cite this

    The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner. / Nakamura-Ishizu, Ayako; Kurihara, Toshihide; Okuno, Yuji; Ozawa, Yoko; Kishi, Kazuo; Goda, Nobuhito; Tsubota, Kazuo; Okano, Hideyuki; Suda, Toshio; Kubota, Yoshiaki.

    In: Developmental Biology, Vol. 363, No. 1, 01.03.2012, p. 106-114.

    Research output: Contribution to journalArticle

    Nakamura-Ishizu, A, Kurihara, T, Okuno, Y, Ozawa, Y, Kishi, K, Goda, N, Tsubota, K, Okano, H, Suda, T & Kubota, Y 2012, 'The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner', Developmental Biology, vol. 363, no. 1, pp. 106-114. https://doi.org/10.1016/j.ydbio.2011.12.027
    Nakamura-Ishizu, Ayako ; Kurihara, Toshihide ; Okuno, Yuji ; Ozawa, Yoko ; Kishi, Kazuo ; Goda, Nobuhito ; Tsubota, Kazuo ; Okano, Hideyuki ; Suda, Toshio ; Kubota, Yoshiaki. / The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner. In: Developmental Biology. 2012 ; Vol. 363, No. 1. pp. 106-114.
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