Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII
Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII
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血管生成素受体 Tie2 通过调节 COUP-TFII 来实现静脉规范和维护
DOI：
10.7554/elife.21032
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发表时间：
2016-12-22
期刊：
影响因子：
7.7
通讯作者：
He, Yulong
中科院分区：
文献类型：
--
作者：
Chu, Man;Li, Taotao;He, Yulong
静脉发育的机制在很大程度上仍然未知。Tie2信号介导内皮细胞（EC）存活和血管成熟，其激活突变与静脉畸形有关。本研究表明，当Tie2信号在胚胎内皮细胞中普遍或特异性地被Tek靶向删除而减少时，小鼠皮肤和肠系膜中的静脉形成被破坏。出生后Tie2衰减导致新形成的静脉变性，随后在视网膜形成血管瘤样血管丛和静脉扭曲。从机制上讲，Tie2不足损害了静脉EC的特性，正如COUP-TFII蛋白水平显著降低所表明的那样，COUP-TFII蛋白水平是静脉生成的关键调节因子。血管生成素-1刺激在培养的ECs中增加了COUP-TFII，而Tie2敲低或阻断Tie2下游PI3K/Akt通路降低了COUP-TFII，这可以通过蛋白酶体抑制来逆转。总之，我们的研究结果表明，通过Akt介导的COUP-TFII稳定，Tie2对静脉规范和维持至关重要。DOI: http://dx.doi.org/10.7554/eLife.21032.001
Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII. DOI: http://dx.doi.org/10.7554/eLife.21032.001