Integrin α5β1-Ang1/Tie2 receptor cross-talk regulates brain endothelial cell responses following cerebral ischemia.
Integrin α5β1-Ang1/Tie2 receptor cross-talk regulates brain endothelial cell responses following cerebral ischemia.
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整合素α5β1-Ang1/Tie2 受体串扰调节脑缺血后脑内皮细胞反应
DOI：
10.1038/s12276-018-0145-7
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发表时间：
2018-09-05
影响因子：
12.8
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Pang D;Wang L;Dong J;Lai X;Huang Q;Milner R;Li L
我们以前的研究表明，脑缺血时，脑血管中的生长因子血管生成素-1（Ang 1）和α5β1整合素均被诱导，这可能提供了驱动脑缺血后内源性血管生成反应和血管保护的正信号。然而，CI后内皮Ang 1和α5β1整合素之间的确切关系仍然知之甚少。本研究在体内外研究了Ang 1/Tie 2系统与α5β1整合素相互作用对脑缺血条件下脑内皮细胞（BEC）的影响。免疫荧光分析显示整合素α5β1与Tie 2/磷酸化Tie 2共定位于脑血管半影区。体外研究表明，氧糖剥夺/恢复（OGD/R）可诱导BEC上Ang 1受体Tie 2的表达，其表达方式与OGD/R诱导整合素α5和Ang 1的表达方式相似，并伴有Tie 2及其下游效应子粘着斑激酶（FAK）和Akt的激活增加。α5整联蛋白的敲低显着抑制了OGD/R诱导的BEC中Tie 2受体的活化，而相比之下，用Ang 1引发BEC可促进OGD处理的BEC中α5整联蛋白以及Tie 2下游转录因子Ets-1的表达。与此一致，Ets-1敲低显著减弱Ang 1介导的α5整合素上调。在功能上，Ang 1诱导OGD后BEC的细胞迁移和管形成，但这种作用被BEC中α5整合素水平的降低所抑制。综上所述，我们的数据表明，CI后BEC中Ang 1/Tie 2系统与整合素α5β1发生交叉，这可能有助于CI后内源性血管生成血管保护反应。脑血管细胞表面上的两种分子信号传导系统之间的相互作用可以调节对脑缺血性（CI）中风的反应，在脑缺血性中风中，血液供应以及因此到部分脑的氧气被阻塞（例如血块）中断。由上海第二军医大学公利医院的李龙轩和美国拉霍亚斯克里普斯研究所的理查德米尔纳领导的研究人员使用小鼠和培养细胞来研究这些相互作用。结果表明，细胞表面受体蛋白介导的两个信号系统定位在同一地区的血细胞膜响应CI中风。这些系统之间的分子“交互作用”可能会促进新血管的形成，以修复中风造成的损伤。这些见解可以帮助开发治疗CI中风的药物。
We have previously demonstrated that in response to cerebral ischemia (CI), the growth factor angiopoietin-1 (Ang1) and α5β1 integrin are both induced in cerebral vessels, which likely provide positive signals driving the endogenous angiogenic response and vascular protection after CI. However, the precise relationship between endothelial Ang1 and α5β1 integrin after CI remains poorly understood. Here, we investigated the effects of the interaction between the Ang1/Tie2 system and α5β1 integrin on brain endothelial cells (BECs) under cerebral ischemic conditions in vivo and in vitro. Immunofluorescence analysis demonstrated that integrin α5β1 co-localized with Tie2/phosphorylated Tie2 on cerebral vessels in the penumbra. The in vitro study showed that oxygen–glucose deprivation/restoration (OGD/R) induced the expression of the Ang1 receptor Tie2 on BECs in a manner similar to that for integrin α5 and Ang1 in response to OGD/R, accompanied by increased activation of Tie2 and its downstream effectors focal adhesion kinase (FAK) and Akt. Knockdown of α5 integrin markedly suppressed OGD/R-induced Tie2 receptor activation in BECs, while in contrast, priming BECs with Ang1 promoted the expression of α5 integrin as well as the Tie2 downstream transcription factor Ets-1 in OGD-treated BECs. In line with this, Ets-1 knockdown significantly attenuated Ang1-mediated upregulation of α5 integrin. Functionally, Ang1 induced cell migration and tube formation of BECs after OGD, but this effect was inhibited by diminishment of the levels of α5 integrin in BECs. Taken together, our data indicate that the Ang1/Tie2 system cross-talks with integrin α5β1 in BECs after CI, which may contribute to the endogenous angiogenic vascular protective response following CI. Interactions between two molecular signaling systems on the surface of brain blood vessel cells may regulate the response to cerebral ischemic (CI) strokes, in which the blood supply and hence oxygen to part of the brain is interrupted by blockages, such as blood clots. Researchers led by Longxuan Li at Gongli Hospital, the Second Military Medical University, Shanghai, and Richard Milner at the Scripps Research Institute, La Jolla, USA, used mice and cultured cells to study these interactions. The results suggest that the cell surface receptor proteins that mediate both signaling systems localize in the same area of blood cell membranes in response to a CI stroke. Molecular “cross-talk” between these systems may promote the formation of new blood vessels to repair the damage caused by a stroke. These insights could assist development of drugs to treat CI strokes.
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影响因子：
8.3
作者：
KRUPINSKI, J;KALUZA, J;WANG, JM
通讯作者：
WANG, JM
影响因子：
2.8
作者：
Huang, Qijuan;Chen, Bing;Li, Longxuan
通讯作者：
Li, Longxuan
影响因子：
5.3
作者：
Li, Longxuan;Liu, Fudong;Welser-Alves, Jennifer V.;McCullough, Louise D.;Milner, Richard
通讯作者：
Milner, Richard
缺血性中风后神经发生和血管生成的耦合
影响因子：
2.9
作者：
Ruan L;Wang B;ZhuGe Q;Jin K
通讯作者：
Jin K
影响因子：
3.7
作者：
Dalton AC;Shlamkovitch T;Papo N;Barton WA
通讯作者：
Barton WA