Overexpression of α5β1 integrin and angiopoietin-1 co-operatively promote blood-brain barrier integrity and angiogenesis following ischemic stroke
Overexpression of α5β1 integrin and angiopoietin-1 co-operatively promote blood-brain barrier integrity and angiogenesis following ischemic stroke
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α5β1 整合素和血管生成素-1 的过度表达协同促进缺血性中风后血脑屏障的完整性和血管生成
DOI：
10.1016/j.expneurol.2019.113042
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Li Longxuan（李龙宣）
中科院分区：
文献类型：
--
作者：
Zhang Xinyu;Wang Lu;Liu Xinghui;Feng Gang;Fu Yuan;Milner Richard;Li Longxuan（李龙宣）
我们之前已经证明α5β1整合素与血管生成素-1 (Ang1) / Tie2受体之间的互导在脑缺血卒中（CIS）后半暗区脑内皮血管生成反应的调节中起重要作用。然而，最近的一项研究表明，刺激α5β1整合素也具有增加CIS后血脑屏障（BBB）通透性的潜力，这使人们对α5β1整合素本身是否具有保护缺血性损伤的作用产生了怀疑。鉴于这些相互冲突的作用，本研究的目的是评估α5整合素和Ang1共同过表达对大脑中动脉暂时闭塞90 min缺血后体内和体外血管重塑和修复的影响。我们的研究结果表明，与模拟转染的对照组相比，单独过表达α5整合素并没有改善神经学评分和梗死面积，而且导致缺血半球血脑屏障破坏更严重，抵消了其在CIS早期有益的血管生成作用。然而，α5整合素与Ang1的共过表达导致梗死面积缩小和神经功能缺损改善，这在分子水平上是由缺血半暗带早期血脑屏障破坏减少和内皮紧密连接蛋白表达增加所支持的。此外，α5整合素和Ang1的共过表达可协同促进CIS早期BEC的增殖，导致晚期血管密度增加。α5整合素与Ang1共过表达对内皮细胞增殖和紧密连接蛋白表达的积极影响也在体外得到证实。综上所述，这些数据表明，Ang-1和α5整合素联合过表达对脑缺血损伤具有协同血管保护作用，而不会对血脑屏障的通透性产生负面影响，为CIS提供了一种新的联合治疗方法。
We previously demonstrated that cross-talk between α5β1 integrin and the angiopoietin-1 (Ang1) / Tie2 receptor plays an important role in regulating brain endothelial angiogenic responses in the ischemic penumbra following cerebral ischemic stroke (CIS). However, a recent study suggested that stimulation of the α5β1 integrin also has the potential of increasing blood-brain barrier (BBB) permeability after CIS, raising doubt about whether α5β1 integrin stimulation by itself will protect against ischemic injury. In light of these conflicting roles, the goal of this study was to evaluate the impact of co-overexpression of α5 integrin and Ang1 on vascular remodeling and repair under cerebral ischemic conditions both in vivo following 90 min of ischemia by temporary occlusion of the middle cerebral artery, and in vitro. Our results demonstrate that as compared to mock-transfected controls, overexpression of α5 integrin alone didn't improve the outcomes in neurological score and size of infarct and caused worse BBB breakdown in the ischemic hemisphere, offsetting its beneficial angiogenic effects during the early stages of CIS. However, co-overexpression of α5 integrin with Ang1 led to smaller infarcts and improved neurological deficits, which at the molecular level was underpinned by reduced BBB breakdown and increased expression of endothelial tight junction proteins in the ischemic penumbra during the early stages of CIS. Furthermore, co-overexpression of α5 integrin and Ang1 synergistically promoted BEC proliferation during the early stage of CIS, resulting in increased blood vessel density at later stages. Positive effects of α5 integrin and Ang1 co-overexpression on endothelial proliferation and tight junction protein expression were also confirmed in vitro. Collectively, these data indicate that co-overexpression of Ang-1 and α5 integrin in combination confers synergistic vascular protection against cerebral ischemic injury without the negative side effects on BBB permeability, suggesting a novel combinatorial approach for the treatment of CIS.