Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca2+/NFAT Signaling

被引：148

作者：

Scholz, Beate ^{[1
,2
]}

Korn, Claudia ^{[1
]}

Wojtarowicz, Jessica ^{[1
,2
]}

Mogler, Carolin ^{[1
,3
]}

Augustin, Iris ^{[4
,5
]}

Boutros, Michael ^{[4
,5
]}

Niehrs, Christof ^{[6
,7
]}

Augustin, Hellmut G. ^{[1
,2
,8
]}

机构：

[1] German Canc Res Ctr Heidelberg DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany

[2] Heidelberg Univ, Med Fac Mannheim, Dept Vasc Biol & Tumor Angiogenesis CBTM, D-68167 Mannheim, Germany

[3] Heidelberg Univ, Inst Pathol, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr Heidelberg, Div Signaling & Funct Genom, D-69120 Heidelberg, Germany

[5] Heidelberg Univ, Dept Cell & Mol Biol CBTM, Med Fac Mannheim, D-68167 Mannheim, Germany

[6] German Canc Res Ctr Heidelberg DKFZ ZMBH Alliance, Div Mol Embryol, D-69120 Heidelberg, Germany

[7] DNA Demethylat, DNA Repair & Reprogramming, Inst Mol Biol, D-55128 Mainz, Germany

[8] German Canc Consortium, D-69120 Heidelberg, Germany

来源：

DEVELOPMENTAL CELL | 2016年 / 36卷 / 01期

关键词：

BLOOD-BRAIN-BARRIER; WNT/BETA-CATENIN; MOYAMOYA-DISEASE; ANGIOGENESIS; PATHWAY; CELLS; EXPRESSION; PROLIFERATION; R-SPONDIN3; RECEPTORS;

D O I：

10.1016/j.devcel.2015.12.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 Trim30 alpha. RNF213 targets filamin A and NFAT1 for proteasomal degradation attenuating non-canonical WNT/Ca2+ signaling. Likewise, USP18 and TRIM5 alpha 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 RSPO3driven non-canonical WNT/Ca2+/NFAT signaling as a critical maintenance pathway of the remodeling vasculature.

引用

页码：79 / 93

页数：15

共 53 条

[1] R-spondin3 is required for mouse placental development [J].