Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling.
Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling.
复制标题
DOI：
10.1038/ncb3534
复制
发表时间：
2017-06
影响因子：
21.3
通讯作者：
Jakobsson L
中科院分区：
文献类型：
--
作者：
Jin Y;Muhl L;Burmakin M;Wang Y;Duchez AC;Betsholtz C;Arthur HM;Jakobsson L
内皮细胞 (EC) 富集基因内皮糖蛋白 (ENG) 的功能丧失 (LOF) 突变会导致人类疾病遗传性出血性毛细血管扩张-1，其特征是血管内皮生长因子 A (VEGFA) 促进的血管畸形。 ENG 缺陷如何改变 EC 行为以触发这些异常尚不清楚。出生后小鼠中的马赛克 ENG 缺失使得 Eng LOF ECs 对血流介导的静脉到动脉迁移不敏感。保留在小动脉内的 Eng LOF ECs 获得了静脉特征和继发性 ENG 独立增殖，导致动静脉畸形 (AVM)。同时进行 Eng LOF 和过表达 (OE) 后的分析表明，ENG OE EC 主导尖端细胞位置并优先归巢于动脉。 ENG 敲低改变了 VEGFA 介导的 VEGFR2 动力学并促进 AKT 信号传导。 PI3K/AKT 的阻断可部分正常化体外 ENG LOF EC 的流向迁移，并降低体内 AVM 的严重程度。这证明了 ENG 在血流介导的迁移和血管模式中 VEGFR2 信号传导的调节中的需要。
Loss-of-function (LOF) mutations in the endothelial cell (EC) enriched gene endoglin (ENG) causes the human disease hereditary haemorrhagic telangiectasia-1, characterized by vascular malformations promoted by vascular endothelial growth factor A (VEGFA). How ENG deficiency alters EC behaviour to trigger these anomalies is not understood. Mosaic ENG deletion in the postnatal mouse rendered Eng LOF ECs insensitive to flow-mediated venous to arterial migration. Eng LOF ECs retained within arterioles acquired venous characteristics and secondary ENG-independent proliferation resulting in arterio-venous malformation (AVM). Analysis following simultaneous Eng LOF and overexpression (OE) revealed that ENG OE ECs dominate tip cell positions and home preferentially to arteries. ENG knock-down altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI3K/AKT partly normalised flow-directed migration of ENG LOF ECs in vitro and reduced the severity of AVM in vivo. This demonstrates the requirement of ENG in flow-mediated migration and modulation of VEGFR2 signalling in vascular patterning.