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

作者：Kurihara Toshihide; Westenskow Peter D; Krohne Tim U; Aguilar Edith; Johnson Randall S; Friedlander Martin^*

来源：The Journal of Cell Biology, 2011, 195(4): 689-701.

DOI：10.1083/jcb.201107029

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-alpha s (Hif-alpha s), 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-alpha s, and Vegf genes revealed that HIF-2 alpha/vascular endothelial growth factor signaling induces secondary outgrowth in Vhl mutants. Conversely, HIF-1 alpha 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.

• 出版日期2011-11-14