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Dev Cell. 2016 Jan 11;36(1):79-93. doi: 10.1016/j.devcel.2015.12.015.

Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling.

Author information

1
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Straße 13-17, 68167 Mannheim, Germany.
2
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
3
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Institute of Pathology, Heidelberg University, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
4
Division of Signaling and Functional Genomics, German Cancer Research Center Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Cell and Molecular Biology (CBTM), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Straße 13-17, 68167 Mannheim, Germany.
5
Division of Molecular Embryology, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; DNA Demethylation, DNA Repair and Reprogramming, Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany.
6
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Straße 13-17, 68167 Mannheim, Germany; German Cancer Consortium, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: augustin@angiogenese.de.

Abstract

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/Ca(2+) 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/Ca(2+)/NFAT signaling as a critical maintenance pathway of the remodeling vasculature.

KEYWORDS:

Moyamoya; NFAT; R-spondin; RNF213; RSPO3; WNT; angiogenesis; non-canonical WNT pathway; vascular pruning; vascular regression; vascular remodeling

PMID:
26766444
DOI:
10.1016/j.devcel.2015.12.015
[Indexed for MEDLINE]
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