Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis
Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis
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DOI：
10.1242/dev.104422
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发表时间：
2014-04-15
期刊：
影响因子：
4.6
通讯作者：
Augustin, Iris
中科院分区：
文献类型：
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作者：
Korn, Claudia;Scholz, Beate;Augustin, Iris
多种细胞类型参与血管生成表达Wnt配体的调控。尽管β -连环蛋白依赖和独立的Wnt信号通路已被证明可以控制血管生成，但在血管形成过程中，内皮细胞（ECs）中单个细胞类型对激活这些下游通路的贡献仍然是难以捉摸的。为了研究ECs在提供Wnt配体调节血管形成中的作用，我们在小鼠ECs中有条件地删除了Wnt分泌因子Evi （Evi- ecko）。Evi-ECKO小鼠在出生后视网膜和肿瘤的生理性和病理性血管生成过程中分别显示微血管密度下降。微血管密度降低是由于血管退化加剧，同时EC存活和增殖降低。同时，存活相关基因下调，细胞周期阻滞和凋亡诱导基因上调。体外培养的HUVECs中EVI沉默表现出类似的靶基因调控，支持EC衍生的Wnt配体控制EC功能的机制。ECs优先表达非典型Wnt配体，在Evi-ECKO小鼠中，典型靶基因的表达不受影响。此外，引入非规范Wnt5a可以挽救Evi-ECKO小鼠Matrigel桥塞血管化的减少。用非典型Wnt抑制剂TNP470处理小鼠幼崽导致血管退化增加，同时EC增殖减少，从而模仿增殖依赖的Evi-ECKO重塑表型。综上所述，本研究确定了EC衍生的非规范Wnt配体在发育和病理性血管生成过程中作为EC存活、增殖和随后的血管修剪的调节剂。
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.