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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 Article has an altmetric score of 3

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 1

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Formation of fibronectin-matrix scaffolds in proangiogenic astrocytes. (...
Formation of fibronectin-matrix scaffolds in proangiogenic astrocytes. (A) Triple immunostaining (top) for fibronectin (FN, green), PECAM-1 (red), and PDGFRα (blue) and double immunostaining (middle and bottom) for lectin (red) and integrin α5 or β1 (green) at the sprouting vascular edges of P5 retina. (B and C) Retinal vessels 24 (B) or 48 (C) hours after intraocular injections of control IgG (left) or anti-integrin β1 antibody (right) at P2. (B) Immunostaining for PECAM-1 (red) and PDGFRα (green) at the sprouting vascular edges. Arrows indicate endothelial cells dissociating from astrocyte (AC) scaffolds. (C) PECAM-1 staining. (D) Immunostaining for PDGFRα (red) and fibronectin (green) in P7 retina. Fibronectin is expressed around blood vessels (arrowheads) but almost absent in astrocyte networks, which are not associated with blood vessels (arrows). (E) Flow cytometric analysis of retinal cells from Tie2-GFP transgenic mice at P7. Endothelial cells and astrocytes were sorted as GFP+ (0.26%) and PDGFRα+ (0.43%) fractions, respectively. (F) RT-PCR from total RNA of GFP+ and PDGFRα+ cells sorted by FACS. Fibronectin mRNA is expressed in both endothelial cells and astrocytes. (G) Red immunostaining for PDGFRα (left), ISH for fibronectin (middle), or VEGF (right) in P4 retinas. Arrowheads indicate the growing edge of the retinal vasculature depicted by immunostaining for type IV collagen (coll IV; green). Lower panels are the magnified views of growing vascular edges. Magnification, ×200 (A and D), ×400 (B), ×70 (C), ×63 (G, upper), ×252 (G, lower).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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