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Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes
Akiyoshi Uemura, … , Ruth T. Yu, Shin-Ichi Nishikawa
Akiyoshi Uemura, … , Ruth T. Yu, Shin-Ichi Nishikawa
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):369-377. https://doi.org/10.1172/JCI25964.
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Research Article Ophthalmology

Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes

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Abstract

In response to hypoxia, hypoxia-inducible factors act as the primary proangiogenic triggers by regulating transcription levels of target genes, including VEGF. However, little is known about the specific factors that control other components of the angiogenic process, particularly formation of matrix scaffolds that promote adhesion and migration of endothelial cells. We show that in the postnatal mouse retina, the orphan nuclear receptor tailless (Tlx) is strongly expressed in the proangiogenic astrocytes, which secrete VEGF and fibronectin. Tlx expression by retinal astrocytes is controlled by oxygen concentration and rapidly downregulated upon contact with blood vessels. In mice null for Tlx, retinal astrocytes maintain VEGF expression; however, the extracellular assembly of fibronectin matrices by astrocytes is severely impaired, leading to defective scaffold formation and a complete failure of normal retinal vascular development. This work identifies Tlx as an essential component of the molecular network involved in the hypoxia-inducible proangiogenic switch in retinal astrocytes.

Authors

Akiyoshi Uemura, Sentaro Kusuhara, Stanley J. Wiegand, Ruth T. Yu, Shin-Ichi Nishikawa

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Figure 5

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Morphogenetic defects in network formation and abortive proangiogenic ac...
Morphogenetic defects in network formation and abortive proangiogenic activities in retinal astrocytes of Tlx KO mice. (A) Immunostaining for PDGFRα in Tlx mutant mice. In Tlx–/– mice, astrocyte networks are poorly extended and morphogenetically disorganized, with fewer branchings. (B) Double labeling for BrdU (red) and PDGFRα (green) of migrating astrocytes in P5 retina. (C and D) Double immunostaining for GFAP (red) and PECAM-1 (green) in P5 retina. GFAP is strongly expressed in all retinal astrocytes of Tlx–/– mice despite the complete absence of blood vessels (C). In Tlx–/– mice, blood vessels never sprout from the stem of hyaloid vessels at optic nerve head (arrowheads in D). Nuclear staining by TO-PRO-3 iodide appears in blue. Magnification, ×70 (A), ×400 (B), ×100 (C), ×280 (D).

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