Tianjin Neurological Institute; Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China.
Department of Neurosurgery, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, China.
J Neurotrauma. 2022 Jun;39(11-12):879-890. doi: 10.1089/neu.2021.0274.
Traumatic brain injury (TBI) impairs cerebrovascular autoregulation and reduces cerebral blood flow (CBF), leading to ischemic secondary injuries. We have shown that injured brains release brain-derived extracellular vesicles (BDEVs) into circulation, where they cause a systemic hypercoagulable state that rapidly turns into consumptive coagulopathy. The BDEVs induce endothelial injury and permeability, leading to the hypothesis that they contribute to TBI-induced cerebrovascular dysregulation. In a study designed to test this hypothesis, we detected circulating BDEVs in C57BL/6J mice subjected to severe TBI, reaching peak levels of 3 × 10/μL at 3 h post-injury (71.2 ± 21.5% of total annexin V-binding EVs). We further showed in an adaptive transfer model that 41.7 ± 5.8% of non-injured mice died within 6 h after being infused with 3 × 10/μL of BDEVs. The BDEVs transmigrated through the vessel walls, induced rapid vasoconstriction by inducing calcium influx in vascular smooth muscle cells, and reduced CBF by 93.8 ± 5.6% within 30 min after infusion. The CBF suppression was persistent in mice that eventually died, but it recovered quickly in surviving mice. It was prevented by the calcium channel blocker nimodipine. When being separated, neither protein nor phospholipid components from the lethal number of BDEVs induced vasoconstriction, reduced CBF, and caused death. These results demonstrate a novel vasoconstrictive activity of BDEVs that depends on the structure of BDEVs and contributes to TBI-induced disseminated cerebral ischemia and sudden death.
创伤性脑损伤 (TBI) 会损害脑血管自动调节功能并降低脑血流量 (CBF)，导致缺血性继发性损伤。我们已经表明，受损的大脑会将脑源性细胞外囊泡 (BDEVs) 释放到循环中，在循环中它们会引起全身性高凝状态，这种状态很快转变为消耗性凝血病。BDEVs 会引起内皮损伤和通透性，这导致了它们可能导致 TBI 引起的脑血管失调的假说。在一项旨在检验这一假说的研究中，我们在 C57BL/6J 小鼠中检测到了 TBI 后的循环 BDEVs，在损伤后 3 小时达到峰值水平，为 3×10/μL（总膜联蛋白 V 结合 EVs 的 71.2±21.5%）。我们进一步在适应性转移模型中表明，在输注 3×10/μL BDEVs 后，41.7±5.8%的非损伤小鼠在 6 小时内死亡。BDEVs 穿过血管壁，通过诱导血管平滑肌细胞内钙流入来诱导快速血管收缩，并在输注后 30 分钟内使 CBF 降低 93.8±5.6%。在最终死亡的小鼠中，CBF 抑制持续存在，但在存活的小鼠中很快恢复。钙通道阻滞剂尼莫地平可预防这种情况。当分离时，来自致死数量的 BDEVs 的既不是蛋白质也不是磷脂成分引起血管收缩、降低 CBF 和导致死亡。这些结果表明 BDEVs 具有一种新型的血管收缩活性，这取决于 BDEVs 的结构，并有助于 TBI 引起的弥散性脑缺血和猝死。
