Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury
Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury
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DOI：
10.1016/j.expneurol.2019.03.014
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Abdul-Muneer, P. M.
中科院分区：
文献类型：
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作者：
Bhowmick, Saurav;D'Mello, Veera;Abdul-Muneer, P. M.
血脑屏障（BBB）由微血管内皮细胞、周细胞和星形胶质细胞组成。脑周细胞是BBB完整性、渗透性和血流的重要调节者。周细胞损失与损伤有关;然而，周细胞、内皮细胞和星形胶质细胞之间的串扰如何最终导致创伤性脑损伤（TBI）中的BBB功能障碍仍然是难以捉摸的。在这项研究中，我们证明了周细胞-内皮细胞相互作用在维持血脑屏障功能中的重要性。TBI引起血小板衍生生长因子-B（PDGF-B）/PDGF受体-β信号传导损伤，其导致与内皮的相互作用丧失并导致神经血管功能障碍。在小鼠体内使用轻度（7 psi）和中度（15 psi）液压冲击损伤（FPI），我们证明了各种周细胞标志物的表达，包括PDGFR-β、NG 2和CD 13，这些标志物的表达显著降低，随后各种整合素的表达降低;粘附连接蛋白，N-钙粘蛋白;间隙连接蛋白，连接蛋白43;以及紧密连接蛋白，例如闭合蛋白、紧密连接蛋白-5、ZO-1和JAM-a。周细胞-内皮细胞相互作用的损害增加了BBB对水的渗透性，其特征在于损伤动物中水通道蛋白4表达的显著增加。同样，FPI动物的周细胞-内皮完整性受损大大增加了小分子量荧光素钠和高分子量示踪剂埃文斯蓝穿过BBB的渗透性。此外，与对照组相比，受伤动物的血液样本中S100 β和NSE水平显着较高。总之，我们的数据提供了一个见解，脑外伤导致周细胞-内皮完整性的早期损害，并导致血脑屏障失调，引发与TBI相关的病理后果。
The blood-brain barrier (BBB) constitutes a neurovascular unit formed by microvascular endothelial cells, pericytes, and astrocytes. Brain pericytes are important regulators of BBB integrity, permeability, and blood flow. Pericyte loss has been implicated in injury; however, how the crosstalk among pericytes, endothelial cells, and astrocytes ultimately leads to BBB dysfunction in traumatic brain injury (TBI) remains elusive. In this study, we demonstrate the importance of pericyte-endothelium interaction in maintaining the BBB function. TBI causes the platelet-derived growth factor-B (PDGF-B)/PDGF receptor-beta signaling impairment that results in loss of interaction with endothelium and leads to neurovascular dysfunction. Using in vivo mild (7 psi) and moderate (15 psi) fluid percussion injury (FPI) in mice, we demonstrate the expression of various pericyte markers including PDGFR-beta, NG2 and CD13 that were significantly reduced with a subsequent reduction in the expression of various integrins; adherent junction protein, N-cadherin; gap junction protein, connexin-43; and tight junction proteins such as occludin, claudin-5, ZO-1, and JAM-a. Impairment of pericyte-endothelium interaction increases the BBB permeability to water that is marked by a significant increase in aquaporin4 expression in injured animals. Similarly, pericyte-endothelium integrity impairment in FPI animals greatly increases the permeability of small-molecular-weight sodium fluorescein and high-molecular-weight-tracer Evans blue across the BBB. In addition, the injury-inflicted animals show significantly higher levels of S100 beta and NSE in the blood samples compared with controls. In conclusion, our data provide an insight that brain trauma causes an early impairment of pericyte-endothelium integrity and results in BBB dysregulation that initiates pathological consequences associated with TBI.