Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca2+/NFAT signaling
The WNT signaling enhancer R-spondin3 (RSPO3) is prominently expressed in the vasculature. Correspondingly, embryonic lethality of Rspo3-deficient mice is caused by vessel remodeling defects. Yet the mechanisms underlying vascular RSPO3 function remain elusive. Inducible endothelial Rspo3 deletion (...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 11, 2016
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| In: |
Developmental cell
Year: 2016, Volume: 36, Issue: 1, Pages: 79-93 |
| ISSN: | 1878-1551 |
| DOI: | 10.1016/j.devcel.2015.12.015 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.devcel.2015.12.015 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S153458071500800X 
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| Author Notes: | Beate Scholz, Claudia Korn, Jessica Wojtarowicz, Carolin Mogler, Iris Augustin, Michael Boutros, Christof Niehrs, and Hellmut G. Augustin |
| Summary: | The WNT signaling enhancer R-spondin3 (RSPO3) is prominently expressed in the vasculature. Correspondingly, embryonic lethality of Rspo3-deficient mice is caused by vessel remodeling defects. Yet the mechanisms underlying vascular RSPO3 function remain elusive. Inducible endothelial Rspo3 deletion (Rspo3-iECKO) resulted in perturbed developmental and tumor vascular remodeling. Endothelial cell apoptosis and vascular pruning led to reduced microvessel density in Rspo3-iECKO mice. Rspo3-iECKO mice strikingly phenocopied the non-canonical WNT signaling-induced vascular defects of mice deleted for the WNT secretion factor Evi/Wls. An endothelial screen for RSPO3 and EVI/WLS co-regulated genes identified Rnf213, Usp18, and Trim30α. RNF213 targets filamin A and NFAT1 for proteasomal degradation attenuating non-canonical WNT/Ca2+ signaling. Likewise, USP18 and TRIM5α inhibited NFAT1 activation. Consequently, NFAT protein levels were decreased in endothelial cells of Rspo3-iECKO mice and pharmacological NFAT inhibition phenocopied Rspo3-iECKO mice. The data identify endothelial RSPO3-driven non-canonical WNT/Ca2+/NFAT signaling as a critical maintenance pathway of the remodeling vasculature. |
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| Item Description: | Gesehen am 12.02.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1878-1551 |
| DOI: | 10.1016/j.devcel.2015.12.015 |