Von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina

Toshihide Kurihara, Yoshiaki Kubota, Yoko Ozawa, Keiyo Takubo, Kousuke Noda, M. Celeste Simon, Randall S. Johnson, Makoto Suematsu, Kazuo Tsubota, Susumu Ishida, Nobuhito Goda, Toshio Suda, Hideyuki Okano

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    Abstract

    In early neonates, the fetal circulatory system undergoes dramatic transition to the adult circulatory system. Normally, embryonic connecting vessels, such as the ductus arteriosus and the foramen ovale, close and regress. In the neonatal retina, hyaloid vessels maintaining blood flow in the embryonic retina regress, and retinal vessels take over to form the adult-type circulatory system. This process is regulated by a programmed cell death switch mediated by macrophages via Wnt and angiopoietin 2 pathways. In this study, we seek other mechanisms that regulate this process, and focus on the dramatic change in oxygen environment at the point of birth. The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate recognition component of an E3-ubiquitin ligase that rapidly destabilizes hypoxia-inducible factor as (HIF-αs) under normoxic, but not hypoxic, conditions. To examine the role of oxygen-sensing mechanisms in retinal circulatory system transition, we generated retina-specific conditional-knockout mice for VHL (Vhl α-CreKO mice). These mice exhibit arrested transition from the fetal to the adult circulatory system, persistence of hyaloid vessels and poorly formed retinal vessels. These defects are suppressed by intraocular injection of FLT1-Fc protein [a vascular endothelial growth factor (VEGF) receptor-1 (FLT1)/Fc chimeric protein that can bind VEGF and inhibit its activity], or by inactivating the HIF-1a gene. Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina.

    Original languageEnglish
    Pages (from-to)1563-1571
    Number of pages9
    JournalDevelopment
    Volume137
    Issue number9
    DOIs
    Publication statusPublished - 2010 May 1

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    Cardiovascular System
    Retina
    Retinal Vessels
    Proteins
    Oxygen
    Von Hippel-Lindau Tumor Suppressor Protein
    Macrophages
    Angiopoietin-2
    Intraocular Injections
    Foramen Ovale
    Vascular Endothelial Growth Factor Receptor-1
    Ductus Arteriosus
    Ubiquitin-Protein Ligases
    Knockout Mice
    Vascular Endothelial Growth Factor A
    Blood Vessels
    Cell Death
    Parturition
    Genes

    Keywords

    • Angiogenesis
    • Circulatory system
    • Hypoxia-inducible factor 1
    • Mouse

    ASJC Scopus subject areas

    • Developmental Biology
    • Molecular Biology
    • Medicine(all)

    Cite this

    Kurihara, T., Kubota, Y., Ozawa, Y., Takubo, K., Noda, K., Simon, M. C., ... Okano, H. (2010). Von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. Development, 137(9), 1563-1571. https://doi.org/10.1242/dev.049015

    Von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. / Kurihara, Toshihide; Kubota, Yoshiaki; Ozawa, Yoko; Takubo, Keiyo; Noda, Kousuke; Simon, M. Celeste; Johnson, Randall S.; Suematsu, Makoto; Tsubota, Kazuo; Ishida, Susumu; Goda, Nobuhito; Suda, Toshio; Okano, Hideyuki.

    In: Development, Vol. 137, No. 9, 01.05.2010, p. 1563-1571.

    Research output: Contribution to journalArticle

    Kurihara, T, Kubota, Y, Ozawa, Y, Takubo, K, Noda, K, Simon, MC, Johnson, RS, Suematsu, M, Tsubota, K, Ishida, S, Goda, N, Suda, T & Okano, H 2010, 'Von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina', Development, vol. 137, no. 9, pp. 1563-1571. https://doi.org/10.1242/dev.049015
    Kurihara, Toshihide ; Kubota, Yoshiaki ; Ozawa, Yoko ; Takubo, Keiyo ; Noda, Kousuke ; Simon, M. Celeste ; Johnson, Randall S. ; Suematsu, Makoto ; Tsubota, Kazuo ; Ishida, Susumu ; Goda, Nobuhito ; Suda, Toshio ; Okano, Hideyuki. / Von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. In: Development. 2010 ; Vol. 137, No. 9. pp. 1563-1571.
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