Repository logo
 

Astrocyte pVHL and HIF-α isoforms are required for embryonic-to-adult vascular transition in the eye.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Kurihara, Toshihide 
Westenskow, Peter D 
Krohne, Tim U 
Aguilar, Edith 
Johnson, Randall S 

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.

Description

Keywords

Animals, Astrocytes, Eye, Gene Deletion, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Isoforms, Tissue Culture Techniques, Vascular Endothelial Growth Factors, Von Hippel-Lindau Tumor Suppressor Protein

Journal Title

J Cell Biol

Conference Name

Journal ISSN

0021-9525
1540-8140

Volume Title

195

Publisher

Rockefeller University Press
Sponsorship
Wellcome Trust (092738/Z/10/Z)