AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses.
AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses.
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AIP1 介导血管内皮细胞生长因子受体 3 依赖性血管生成和淋巴管生成反应
DOI：
10.1161/atvbaha.113.303053
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Zhou HJ;Chen X;Huang Q;Liu R;Zhang H;Wang Y;Jin Y;Liang X;Lu L;Xu Z;Min W
研究AIP 1在VEGFR-3信号转导、VEGFR-3依赖性血管生成和淋巴管生成中的新功能。AIP 1是一种信号支架蛋白，在血管内皮中高度表达。我们以前报道过AIP 1通过阻断VEGFR-2活性在病理性血管生成中作为内源性抑制剂发挥作用。令人惊讶的是，在这里我们观察到具有AIP 1的整体缺失（AIP 1-KO）的小鼠表现出减少的视网膜血管生成，具有较少的发芽和较少的分支。血管内皮细胞（而非神经元）特异性AIP 1缺失导致视网膜血管生成类似缺陷。尽管AIP 1-KO视网膜中VEGFR-2水平增加，但视网膜血管生成减少与VEGFR-3表达减少相关。与VEGFR-3表达减少一致，AIP 1-KO小鼠在新生儿皮肤和肠系膜中显示出延迟的淋巴管生成发育，并且VEGF-C诱导的角膜淋巴管生成较弱。在体外，具有AIP 1 siRNA敲低的人淋巴EC、视网膜EC和从AIP 1-KO分离的淋巴EC都显示减弱的VEGF-C诱导的VEGFR-3信号传导。从机制上讲，我们证明AIP 1通过vegfr-3特异性miR-1236增加VEGFR-3蛋白表达，并通过直接结合VEGFR-3增强VEGFR-3的内吞作用和稳定性。我们在体内和体外的结果提供了第一个洞察AIP 1介导的VEGFR-3依赖的血管生成和淋巴管生成信号的机制。
To investigate the novel function of AIP1 in VEGFR-3 signaling, and VEGFR-3-dependent angiogenesis and lymphangiogenesis. AIP1, a signaling scaffold protein, is highly expressed in the vascular endothelium. We have previously reported that AIP1 functions as an endogenous inhibitor in pathological angiogenesis by blocking VEGFR-2 activity. Surprisingly, here we observe that mice with a global deletion of AIP1 (AIP1-KO) exhibit reduced retinal angiogenesis with less sprouting and fewer branches. Vascular endothelial cell (but not neuronal)-specific deletion of AIP1 causes similar defects in retinal angiogenesis. The reduced retinal angiogenesis correlates with reduced expression in VEGFR-3 despite increased VEGFR-2 levels in AIP1-KO retinas. Consistent with the reduced expression of VEGFR-3, AIP1-KO mice show delayed developmental lymphangiogenesis in neonatal skin and mesentery, and mount weaker VEGF-C-induced cornea lymphangiogenesis. In vitro, human lymphatic EC with AIP1 siRNA knockdown, retinal EC and lymphatic EC isolated from AIP1-KO all show attenuated VEGF-C-induced VEGFR-3 signaling. Mechanistically, we demonstrate that AIP1 via vegfr-3-specific miR-1236 increases VEGFR-3 protein expression, and by directly binding to VEGFR-3 enhances VEGFR-3 endocytosis and stability. Our in vivo and in vitro results provide the first insight into the mechanism by which AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic signaling.