The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner.
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.
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Ayako
A
Nakamura-Ishizu
Toshihide
T
Kurihara
Yuji
Y
Okuno
Yoko
Y
Ozawa
Kazuo
K
Kishi
Nobuhito
N
Goda
Kazuo
K
Tsubota
Hideyuki
H
Okano
Toshio
T
Suda
Yoshiaki
Y
Kubota
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic; D010100:Oxygen / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D055351:Retinal Neurons / Q000378:metabolism; D012171:Retinal Vessels / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D049452:Green Fluorescent Proteins; D010100:Oxygen