Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury
Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury
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DOI：
10.1523/jneurosci.0914-18.2018
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发表时间：
2018-11-07
影响因子：
5.3
通讯作者：
Theus, Michelle H.
中科院分区：
文献类型：
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作者：
Brickler, Thomas R.;Hazy, Amanda;Theus, Michelle H.
尽管受伤年龄影响创伤性脑损伤(TBI)的慢性康复，但年龄对早期结果的不同影响仍未得到充分研究。采用雄性小鼠中度挫伤模型，研究了S对幼年和成年脑挫裂伤不同反应的调控机制。我们展示了幼稚的青少年和成人大脑相似的生物力学和物理特性。然而，在受控皮质撞击(CCI)后，幼鼠在第4天和第14天表现出皮质损伤形成、细胞死亡和行为缺陷的减少。高分辨率激光多普勒成像分析显示，CCI后3和24小时同侧皮质的脑血流(CBF)损失相似，而幼鼠在2-4天表现出比成年鼠更强的随后恢复。这些发现与血脑屏障(BBB)破坏减少和病灶周围血管密度增加有关。为了解决年龄依赖的内皮细胞(EC)反应是否影响血管稳定性和组织结果，我们从假手术和损伤的皮质中磁分离CD31(+)内皮细胞，并评估mRNA的表达。有趣的是，我们发现，与成年人相比，青少年血脑屏障稳定性相关基因的转录增加，而血脑屏障干扰基因的表达减少。这些差异伴随着miRNA-21-5p和miR-148A水平的显著变化。伴随这些发现的是强大的GFAP免疫反应，到第35天还没有解决。重要的是，药物抑制EC特异性的Tie2信号消除了幼虫的保护作用。这些发现为年龄对急性脑外伤预后的不同影响提供了新的机制，这些影响既有空间上的，也有时间上的。
Although age-at-injury influences chronic recovery from traumatic brain injury (TBI), the differential effects of age on early outcome remain understudied. Using a male murine model of moderate contusion injury, we investigated the underlying mechanism(s) regulating the distinct response between juvenile and adult TBI. We demonstrate similar biomechanical and physical properties of naive juvenile and adult brains. However, following controlled cortical impact (CCI), juvenile mice displayed reduced cortical lesion formation, cell death, and behavioral deficits at 4 and 14 d. Analysis of high-resolution laser Doppler imaging showed a similar loss of cerebral blood flow (CBF) in the ipsilateral cortex at 3 and 24 h post-CCI, whereas juvenile mice showed enhanced subsequent restoration at 2-4 d compared with adults. These findings correlated with reduced blood-brain barrier (BBB) disruption and increased perilesional vessel density. To address whether an age-dependent endothelial cell (EC) response affects vessel stability and tissue outcome, we magnetically isolated CD31(+) ECs from sham and injured cortices and evaluated mRNA expression. Interestingly, we found increased transcripts for BBB stability-related genes and reduced expression of BBB-disrupting genes in juveniles compared with adults. These differences were concomitant with significant changes in miRNA-21-5p and miR-148a levels. Accompanying these findings was robust GFAP immunoreactivity, which was not resolved by day 35. Importantly, pharmacological inhibition of EC-specific Tie2 signaling abolished the juvenile protective effects. These findings shed new mechanistic light on the divergent effects that age plays on acute TBI outcome that are both spatial and temporal dependent.