FVIIa PREVENTS THE PROGRESSIVE HEMORRHAGING OF A BRAIN CONTUSION BY PROTECTING MICROVESSELS VIA FORMATION OF THE TF-FVIIa-FXa COMPLEX
FVIIa PREVENTS THE PROGRESSIVE HEMORRHAGING OF A BRAIN CONTUSION BY PROTECTING MICROVESSELS VIA FORMATION OF THE TF-FVIIa-FXa COMPLEX
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FVIIa 通过形成 TF-FVIIa-FXa 复合物来保护微血管，从而防止脑挫裂伤的进行性出血
DOI：
10.1016/j.neuroscience.2017.02.020
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发表时间：
2017
期刊：
影响因子：
3.3
通讯作者：
Hu Jin
中科院分区：
文献类型：
--
作者：
Yuan Qiang;Zhang Dalong;Wu Sirong;Yu Jian;Yu Lei;Sun Yirui;Du Zhuoying;Li Zhiqi;Zhou Liangfu;Wu Xing;Hu Jin
因子VII（FVII）在凝血级联的启动中起关键作用，并且在临床情况下，重组人活化FVII（rFVIIa）有效地防止脑挫伤后的进行性脑水肿。然而，目前尚不清楚FVII活性的降低是否直接导致进行性骨老化，此外，这一过程的确切机制尚不清楚。本研究表明，FVII活性降低直接导致脑挫伤的进行性再灌注。FVII的给药通过保护挫伤半影区的微血管内皮细胞来防止脑挫伤出血的进展。本研究还表明，TF-FVIIa-FXa三元复合物切割内皮细胞上的内源性蛋白酶激活受体2（PAR 2），激活p44/42丝裂原激活蛋白激酶（MAPK）信号级联，并抑制p65核因子-κB（NF-κB）信号传导。此外，暴露于三元TF-FVIIa-FXa保护内皮细胞免于凝血酶或炎性精氨酸诱导的凋亡。尽管p44/42 MAPK信号通路的激活是内皮细胞蛋白C受体（EPCR）依赖性的，但p65 NF-κB信号通路的抑制是EPCR非依赖性的;因此，TF-FVIIa-FXa在血管内皮细胞中作用的调节机制似乎是多种信号通路。总之，本研究结果表明，FVIIa通过形成三元TF-FVIIa-FXa复合物保护微血管内皮细胞来预防脑挫伤的进行性再狭窄。这些发现是新颖的，具有重要的临床意义，因为FVIIa用于预防人类脑挫伤的进行性脑损伤。
Factor VII (FVII) plays a key role in the initiation of the coagulation cascade and, in clinical situations, recombinant human activated FVII (rFVIIa) effectively prevents progressive hemorrhaging after a brain contusion. However, it remains unclear whether decreases in FVII activity directly lead to progressive hemorrhaging and, moreover, the precise mechanisms underlying this process are not yet known. The present study demonstrated that decreased FVII activity directly led to progressive hemorrhaging of the cerebral contusions. Administration of FVII prevented the progression of hemorrhaging from cerebral contusions by protecting microvessel endothelial cells in the penumbra of the contusion. The present study also showed that the ternary TF–FVIIa–FXa complex cleaved endogenous protease-activated receptor 2 (PAR2) on endothelial cells, activated the p44/42 mitogen-activated protein kinase (MAPK) signaling cascade, and inhibited p65 nuclear factor-κB (NF-κB) signaling. Furthermore, exposure to ternary TF–FVIIa–FXa protected endothelial cells from thrombin- or inflammatory cytokine-induced apoptosis. Although activation of the p44/42 MAPK signaling pathway is endothelial cell protein C receptor (EPCR)-dependent, inhibition of the p65 NF-κB signaling pathway is EPCR-independent; thus, the regulation mechanism underlying the effects of TF–FVIIa–FXa in vascular endothelial cells appears to be multiple signaling pathways. In summary, the present findings demonstrated that FVIIa prevented the progressive hemorrhaging of brain contusions by protecting microvessel endothelial cells via the formation of the ternary TF–FVIIa–FXa complex. These findings are novel and of great clinical significance because FVIIa is used to prevent the progressive hemorrhaging of brain contusions in humans.