Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

被引：102

作者：

Korn, Claudia ^{[1
]}

Scholz, Beate ^{[1
,2
]}

Hu, Junhao ^{[1
]}

Srivastava, Kshitij ^{[1
,2
]}

Wojtarowicz, Jessica ^{[1
,2
]}

Arnsperger, Tabea ^{[1
,3
]}

Adams, Ralf H. ^{[4
,5
]}

Boutros, Michael ^{[3
,6
]}

Augustin, Hellmut G. ^{[1
,2
,7
]}

Augustin, Iris ^{[3
,6
]}

机构：

[1] ZMBH Alliance, German Canc Res Ctr DKFZ, Div Vasc Oncol & Metastasis, D-69221 Heidelberg, Germany

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

[3] German Canc Res Ctr, Div Signaling & Funct Gen, D-69221 Heidelberg, Germany

[4] Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany

[5] Univ Munster, Fac Med, D-48149 Munster, Germany

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

[7] German Canc Consortium, D-69221 Heidelberg, Germany

来源：

DEVELOPMENT | 2014年 / 141卷 / 08期

关键词：

Angiogenesis; Evi; Vessel regression; Wnt; Mouse; BLOOD-BRAIN-BARRIER; INHIBITION; PATHWAY; EXPRESSION; TNP-470; DIFFERENTIATION; FUMAGILLIN; REGRESSION; SURVIVAL; VESSELS;

D O I：

10.1242/dev.104422

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Multiple cell types involved in the regulation of angiogenesis express Wnt ligands. Although beta-catenin dependent and independent Wnt signaling pathways have been shown to control angiogenesis, the contribution of individual cell types to activate these downstream pathways in endothelial cells (ECs) during blood vessel formation is still elusive. To investigate the role of ECs in contributing Wnt ligands for regulation of blood vessel formation, we conditionally deleted the Wnt secretion factor Evi in mouse ECs (Evi-ECKO). Evi-ECKO mice showed decreased microvessel density during physiological and pathological angiogenesis in the postnatal retina and in tumors, respectively. The reduced microvessel density resulted from increased vessel regression accompanied by decreased EC survival and proliferation. Concomitantly, survival-related genes were downregulated and cell cycle arrest- and apoptosis-inducing genes were upregulated. EVI silencing in cultured HUVECs showed similar target gene regulation, supporting a mechanism of EC-derived Wnt ligands in controlling EC function. ECs preferentially expressed non-canonical Wnt ligands and canonical target gene expression was unaffected in Evi-ECKO mice. Furthermore, the reduced vascularization of Matrigel plugs in Evi-ECKO mice could be rescued by introduction of non-canonical Wnt5a. Treatment of mouse pups with the non-canonical Wnt inhibitor TNP470 resulted in increased vessel regression accompanied by decreased EC proliferation, thus mimicking the proliferation-dependent Evi-ECKO remodeling phenotype. Taken together, this study identified EC-derived non-canonical Wnt ligands as regulators of EC survival, proliferation and subsequent vascular pruning during developmental and pathological angiogenesis.

引用

页码：1757 / 1766

页数：10

共 39 条

[11] Wntless is required for peripheral lung differentiation and pulmonary vascular development [J].