Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice.
Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice.
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DOI：
10.3389/fphar.2021.708469
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发表时间：
2021
影响因子：
5.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Cheng C;Wang X;Jiang Y;Li Y;Liao Z;Li W;Yu Z;Whalen MJ;Lok J;Dumont AS;Liu N;Wang X
微血管衰竭是创伤性脑损伤（TBI）后动态病理演变的关键致病因素之一。我们的实验室和其他人之前报道了膜联蛋白A2在血脑屏障（BBB）发育和脑血管生成中起作用，重组人膜联蛋白A2 （rA2）在体外对缺氧和il -1β诱导的脑跨内皮通透性有保护作用，在体内对AXNA2敲除小鼠的脑血管生成损伤有保护作用。因此，我们假设ANXA2可能是一种针对脑外伤后早期血脑屏障完整性破坏和亚急性/延迟脑血管重塑的脑血管治疗候选药物，最终改善神经系统预后。在控制皮质冲击（CCI）小鼠模型中，我们发现rA2治疗（1 mg/kg）可显著减少脑外伤后24小时早期血脑屏障破坏；每天使用rA2治疗7天后，tbi诱导的脑微血管促血管生成因子和内皮源性营养因子mRNA水平升高。在培养的人脑微血管内皮细胞（HBMEC）中，通过MAPKs阵列，我们发现rA2显著激活Akt、ERK和CREB，激活的CREB可能与rA2诱导的VEGF和BDNF表达有关。此外，给药rA2显著增加小鼠脑外伤后14天的脑血管新生和28天的血管密度。我们的结果一致地证实，rA2显著诱导体外血管生成，证明了在HBMEC中的管形成和划痕迁移实验。最后，我们证明了rA2改善了长期感觉运动和认知功能，并减少了TBI后28天的脑组织损失。我们的研究结果表明，rA2可能是治疗创伤性脑损伤的一种新的血管靶向方法。
Microvascular failure is one of the key pathogenic factors in the dynamic pathological evolution after traumatic brain injury (TBI). Our laboratory and others previously reported that Annexin A2 functions in blood-brain barrier (BBB) development and cerebral angiogenesis, and recombinant human Annexin A2 (rA2) protected against hypoxia plus IL-1β-induced cerebral trans-endothelial permeability in vitro, and cerebral angiogenesis impairment of AXNA2 knock-out mice in vivo. We thereby hypothesized that ANXA2 might be a cerebrovascular therapy candidate that targets early BBB integrity disruption, and subacute/delayed cerebrovascular remodeling after TBI, ultimately improve neurological outcomes. In a controlled cortex impact (CCI) mice model, we found rA2 treatment (1 mg/kg) significantly reduced early BBB disruption at 24 h after TBI; and rA2 daily treatment for 7 days augmented TBI-induced mRNA levels of pro-angiogenic and endothelial-derived trophic factors in cerebral microvessels. In cultured human brain microvascular endothelial cells (HBMEC), through MAPKs array, we identified that rA2 significantly activated Akt, ERK, and CREB, and the activated CREB might be responsible for the rA2-induced VEGF and BDNF expression. Moreover, rA2 administration significantly increased cerebral angiogenesis examined at 14 days and vessel density at 28 days after TBI in mice. Consistently, our results validated that rA2 significantly induced angiogenesis in vitro, evidenced by tube formation and scratched migration assays in HBMEC. Lastly, we demonstrated that rA2 improved long-term sensorimotor and cognitive function, and reduced brain tissue loss at 28 days after TBI. Our findings suggest that rA2 might be a novel vascular targeting approach for treating TBI.
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