title: Astrocyte pVHL and HIF-α isoforms are required for embryonic-to-adult vascular transition in the eye.
abstract: Successful transition from embryonic to adult circulation is critical for survival of mammalian organisms. This shift occurs in the central cardiovascular circulation and in the eye as oxygen tension increases. However, its regulation is not well understood. We have used combinatorial gene deletion and overexpression assays to assess the effect of astrocyte-targeted deletion of von Hippel-Lindau tumor suppressor (Vhl), hypoxia-inducible factor-αs (Hif-αs), and Vegf on the normal regression of the hyaloidal vessels, the fetal ocular circulation system. Astrocytic Vhl deletion induced accelerated hyaloidal regression and subsequent massive secondary outgrowth. Combinatorial gene deletion involving Vhl, Hif-αs, and Vegf genes revealed that HIF-2α/vascular endothelial growth factor signaling induces secondary outgrowth in Vhl mutants. Conversely, HIF-1α regulated macrophage migration inhibitory factor and promoted macrophage infiltration that accelerates hyaloidal vessel regression. The phenotype observed in Vhl mutants strongly resembles human persistent hyperplastic primary vitreous cases and may provide insights into vascular remodeling mechanisms in other systems.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.forename: Peter D
authors.initials: PD
authors.lastname: Westenskow
authors.forename: Tim U
authors.initials: TU
authors.lastname: Krohne
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D005123:Eye / Q000098:blood supply* / Q000196:embryology / Q000254:growth & development; D017353:Gene Deletion; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse
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