Insulin-like Growth Factor (IGF)-1 treatment stabilizes the microvascular cytoskeleton under ischemic conditions.
Insulin-like Growth Factor (IGF)-1 treatment stabilizes the microvascular cytoskeleton under ischemic conditions.
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DOI：
10.1016/j.expneurol.2018.09.016
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发表时间：
2019-01
影响因子：
5.3
通讯作者：
Sohrabji F
中科院分区：
文献类型：
--
作者：
Bake S;Okoreeh A;Khosravian H;Sohrabji F
我们前期的研究表明，胰岛素样生长因子（IGF）-1可降低中年雌性大鼠的血脑屏障通透性，并减少大脑中动脉闭塞（MCAo）引起的梗塞体积。同样，来自中年雌性大鼠的原代脑微血管内皮细胞的培养物并暴露于中风样条件（缺氧葡萄糖；OGD），证实IGF-1减少了穿过该细胞单层的染料转移。令人惊讶的是，IGF-1 并没有减弱 OGD 引起的内皮细胞死亡。为了协调这些发现，本研究测试了以下假设：在缺血的最早阶段，IGF-1 通过增加锚定和稳定存活内皮细胞的细胞几何形状来促进屏障功能。在 IGF-1、IGF-1+JB-1（IGFR 抑制剂）或载体存在的情况下，对人脑微血管内皮细胞培养物进行氧糖剥夺（OGD）。 OGD 破坏了细胞单层并减少了细胞间相互作用，这种相互作用在 IGF-1 处理的培养物中得到保留，并通过与 JB-1 同时处理而逆转。 IGF-1 介导的内皮单层保存被 LY294002 治疗逆转，但雷帕霉素则不然，表明 IGF-1 对细胞-细胞接触的作用可能是通过 PI3K 途径介导的。在体内，评估了中年雌性大鼠的微血管形态，这些大鼠通过MCAo进行缺血，并在再灌注后用IGF-I、IGF-1 + JB-1或人工CSF（aCSF；媒介物）处理ICV。与载体对照相比，IGF-1治疗的动物在梗塞周围区域表现出更大的微血管直径，并且纽蛋白（一种锚定蛋白）的染色密度增加。这两项措施均被同时 IGF-1+JB-1 治疗所逆转。此外，这些效果仅限于缺血再灌注后 24 小时，并且在中风后 5 天没有观察到治疗效果。总的来说，这些数据表明，在缺血期间的最初几个小时，IGF-I 促进受体介导的内皮细胞锚定，并且其作用可以准确地表征为血管保护作用。
Our previous studies showed that Insulin-like Growth Factor (IGF)-1 reduced blood brain barrier pemeability and decreased infarct volume caused by middle cerebral artery occlusion (MCAo) in middle aged female rats. Similarly, cultures of primary brain microvessel endothelial cells from middle-aged female rats and exposed to stroke-like conditions (oxygen glucose deprivation; OGD) confirmed that IGF-1 reduced dye transfer across this cell monolayer. Surprisingly, IGF-1 did not attenuate endothelial cell death caused by OGD. To reconcile these findings, the present study tested the hypothesis that, at the earliest phase of ischemia, IGF-1 promotes barrier function by increasing anchorage and stabilizing cell geometry of surviving endothelial cells. Cultures of human brain microvessel endothelial cells were subject to oxygen-glucose deprivation (OGD) in the presence of IGF-1, IGF-1+JB-1 (IGFR inhibitor) or vehicle. OGD disrupted the cell monolayer and reduced cell-cell interactions, which was preserved in IGF-1-treated cultures and reversed by concurrent treatment with JB-1. IGF-1-mediated preservation of the endothelial monolayer was reversed with LY294002 treatment, but not by Rapamycin, indicating that IGF-1s actions on cell-cell contacts are likely mediated via the PI3K pathway. In vivo, microvessel morphology was evaluated in middle-aged female rats that were subjected to ischemia by MCAo, and treated ICV with IGF-I, IGF-1 + JB-1, or artificial CSF (aCSF; vehicle) after reperfusion. Compared to vehicle controls, IGF-1 treated animals displayed larger microvessel diameters in the peri-infarct area and increased staining density for vinculin, an anchorage protein. Both these measures were reversed by concurrent IGF-1+JB-1 treatment. Moreover these effects were restricted to 24h after ischemia-reperfusion and no treatment effects were seen at 5d post stroke. Collectively, these data suggest that in the earliest hours during ischemia, IGF-I promotes receptor-mediated anchorage of endothelial cells, and its actions may be accurately characterized as vasculoprotective.
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影响因子：
4.8
作者：
Bake, Shameena;Okoreeh, Andre K.;Sohrabji, Farida
通讯作者：
Sohrabji, Farida
影响因子：
3.3
作者：
de Geyter, D.;Stoop, W.;Kooijman, R.
通讯作者：
Kooijman, R.
影响因子：
6.2
作者：
Hernandez-Garzon, Edwin;Fernandez, Ana M.;Torres Aleman, Ignacio
通讯作者：
Torres Aleman, Ignacio
影响因子：
7.4
作者：
Guo, Jiabin;Duckles, Sue P.;Weiss, John H.;Li, Xuejun;Krause, Diana N.
通讯作者：
Krause, Diana N.
影响因子：
3.3
作者：
Guan, J;Miller, OT;Gluckman, PD
通讯作者：
Gluckman, PD