ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
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DOI：
10.1172/jci39837
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Simons, Michael
中科院分区：
文献类型：
--
作者：
Ren, Bin;Deng, Yong;Simons, Michael
动脉形态发生是一个重要的和知之甚少的过程。特别是，控制动脉形成的信号事件尚未建立。我们评估了ERK 1/2和PI 3 K信号通路之间平衡的改变是否可以刺激小鼠和斑马鱼动脉形态发生缺陷背景下的动脉形成。通过下调PI 3 K活性、抑制Aka但不抑制Akt 2表达或引入组成型活性ERK 1/2构建体，在体外和体内实现了VEGF反应性降低的小鼠EC中ERK 1/2活性的增加。这种ERK 1/2激活的恢复足以恢复粘连蛋白缺陷小鼠和粘连蛋白敲低斑马鱼受损的动脉发育和分支形态发生。同样的方法有效地刺激了成年小鼠的动脉生长，恢复了缺乏连接蛋白的小鼠和缺乏LDL-R和ApoB 48的动脉粥样硬化小鼠的动脉生成。因此，我们得出结论，PI 3 K-ERK 1/2串扰在动脉生长的调节中起着关键作用，并且通过抑制PI 3 K信号通路来增强ERK信号可以有效地刺激动脉生成。
Arterial morphogenesis is an important and poorly understood process. In particular, the signaling events controlling arterial formation have not been established. We evaluated whether alterations in the balance between ERK1/2 and PI3K signaling pathways could stimulate arterial formation in the setting of defective arterial morphogenesis in mice and zebrafish. Increased ERK1/2 activity in mouse ECs with reduced VEGF responsiveness was achieved in vitro and in vivo by downregulating PI3K activity, suppressing Aka but not Akt2 expression, or introducing a constitutively active ERK1/2 construct. Such restoration of ERK1/2 activation was sufficient to restore impaired arterial development and branching morphogenesis in synectin-deficient mice and synectin-knockdown zebrafish. The same approach effectively stimulated arterial growth in adult mice, restoring arteriogenesis in mice lacking synectin and in atherosclerotic mice lacking both LDL-R and ApoB48. We therefore conclude that PI3K-ERK1/2 crosstalk plays a key role in the regulation of arterial growth and that the augmentation of ERK signaling via suppression of the PI3K signaling pathway can effectively stimulate arteriogenesis.