Inhibition of VEGF Signaling Reduces Diabetes-Exacerbated Brain Swelling, but Not Infarct Size, in Large Cerebral Infarction in Mice.
Inhibition of VEGF Signaling Reduces Diabetes-Exacerbated Brain Swelling, but Not Infarct Size, in Large Cerebral Infarction in Mice.
复制标题
DOI：
10.1007/s12975-017-0601-z
复制
发表时间：
2018-10
影响因子：
6.9
通讯作者：
Cho S
中科院分区：
文献类型：
--
作者：
Kim E;Yang J;Park KW;Cho S
鉴于基于临床前神经保护策略的反复翻译失败，本临床前研究重新评估脑肿胀作为糖尿病卒中的重要病理事件，并研究共病增强脑水肿形成的潜在机制。使2型（轻度）、1型（中度）和混合型1/2型（重度）糖尿病小鼠经受短暂局灶性缺血。在卒中后3天评估脑体积、脑肿胀和IgG外渗。在缺血脑中测定血管内皮生长因子（VEGF）-A、内皮特异性分子-1（Esm 1）和VEGF受体2（VEGFR 2）的表达。此外，SU 5416，一种VEGFR 2抑制剂，在1/2型糖尿病小鼠中进行治疗，并确定中风结果。与非糖尿病小鼠相比，所有糖尿病组均显示出更大的梗死体积和脑肿胀，并且肿胀的增加相对于梗死扩大不成比例地更大。与非糖尿病小鼠相比，糖尿病条件下缺血脑中VEGF-A、Esm 1和VEGFR 2的表达显著增加。值得注意的是，在糖尿病小鼠中，VEGFR 2 mRNA水平与脑肿胀呈正相关，但与梗死体积无关。在糖尿病小鼠中用SU 5416治疗显著降低脑肿胀。该研究表明，脑肿胀是糖尿病卒中的主要病理事件，糖尿病增强的脑肿胀的潜在事件包括VEGF信号转导的激活。本研究建议考虑斯托克治疗，主要目的是减少糖尿病受试者的脑肿胀。
In light of repeated translational failures with preclinical neuroprotection based strategies, this pre-clinical study reevaluates brain swelling as an important pathological event in diabetic stroke and investigates underlying mechanism of the comorbidity-enhanced brain edema formation. Type 2 (mild), type 1 (moderate), and mixed type 1/2 (severe) diabetic mice were subjected to transient focal ischemia. Infarct volume, brain swelling, and IgG extravasation were assessed at 3 days post-stroke. Expression of vascular endothelial growth factor (VEGF)-A, endothelial specific molecule-1 (Esm1), and the VEGF receptor 2 (VEGFR2) was determined in the ischemic brain. Additionally, SU5416, a VEGFR2 inhibitor, was treated in the type 1/2 diabetic mice, and stroke outcomes were determined. All diabetic groups displayed bigger infarct volume and brain swelling compared to nondiabetic mice, and the increased swelling was disproportionately larger relative to infarct enlargement. Diabetic conditions significantly increased VEGF-A, Esm1, and VEGFR2 expressions in the ischemic brain compared to nondiabetic mice. Notably, in diabetic mice, VEGFR2 mRNA levels were positively correlated with brain swelling, but not with infarct volume. Treatment with SU5416 in diabetic mice significantly reduced brain swelling. The study shows that brain swelling is a predominant pathological event in diabetic stroke and that an underlying event for diabetes-enhanced brain swelling includes the activation of VEGF signaling. This study suggests consideration of stoke therapies aiming at primarily reducing brain swelling for subjects with diabetes.
登录
查看更多内容
影响因子：
11.2
作者：
Roudnicky, Filip;Poyet, Cedric;Detmar, Michael
通讯作者：
Detmar, Michael
影响因子：
8.3
作者：
Elali, Ayman;Doeppner, Thorsten R.;Hermann, Dirk M.
通讯作者：
Hermann, Dirk M.
影响因子：
8.2
作者：
Hawkins, B. T.;Lundeen, T. F.;Egleton, R. D.
通讯作者：
Egleton, R. D.
影响因子：
8.3
作者：
TOMINAGA, T;OHNISHI, ST
通讯作者：
OHNISHI, ST
缺血性中风后的血管化模式在对照中与糖尿病大鼠相关：与中风恢复相关。
影响因子：
8.3
作者：
Prakash R;Li W;Qu Z;Johnson MA;Fagan SC;Ergul A
通讯作者：
Ergul A