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30.06.2017 | Original Paper | Ausgabe 4/2017 Open Access

Angiogenesis 4/2017

Endothelium-derived fibronectin regulates neonatal vascular morphogenesis in an autocrine fashion

Zeitschrift:
Angiogenesis > Ausgabe 4/2017
Autoren:
Christopher J. Turner, Kwabena Badu-Nkansah, Richard O. Hynes
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10456-017-9563-8) contains supplementary material, which is available to authorized users.

Abstract

Fibronectin containing alternatively spliced EIIIA and EIIIB domains is largely absent from mature quiescent vessels in adults, but is highly expressed around blood vessels during developmental and pathological angiogenesis. The precise functions of fibronectin and its splice variants during developmental angiogenesis however remain unclear due to the presence of cardiac, somitic, mesodermal and neural defects in existing global fibronectin KO mouse models. Using a rare family of surviving EIIIA EIIIB double KO mice, as well as inducible endothelial-specific fibronectin-deficient mutant mice, we show that vascular development in the neonatal retina is regulated in an autocrine manner by endothelium-derived fibronectin, and requires both EIIIA and EIIIB domains and the RGD-binding α5 and αv integrins for its function. Exogenous sources of fibronectin do not fully substitute for the autocrine function of endothelial fibronectin, demonstrating that fibronectins from different sources contribute differentially to specific aspects of angiogenesis.

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Zusatzmaterial
Supplementary Fig. 1 Fibronectin deposition in Fn iKO and Fn AB KO mutants. Whole-mount immunofluorescence staining confirming (a) loss of fibronectin (middle and right panels) in Fn iKO retinas by P6 following tamoxifen injections from P1-P6, and (b) loss of EIIIA expression (left panel), but normal levels of EIIIA/EIIIB− fibronectin (right panel, magenta) around the vasculature in Fn AB KO mice. Scale bars: 50 μm. (AI 14579 kb)
10456_2017_9563_MOESM1_ESM.ai
Supplementary Fig. 2. Confirmation of efficient gene excision in Fn iEC KO mice. Confocal micrograph showing efficient Cdh5(PAC)-CreERT2 mediated activation of the mTmG reporter, in which Cre-mediated excision results in the expression of membrane-bound GFP, in endothelial cells within the retina of a Fn iEC KO mice at P6, following three consecutive tamoxifen injections (from P1-3). Scale bar: 50 μm. (AI 8089 kb)
10456_2017_9563_MOESM2_ESM.ai
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