School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 315020, China.
Biomed Pharmacother. 2021 Nov;143:112200. doi: 10.1016/j.biopha.2021.112200. Epub 2021 Sep 26.
The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20 (FGF20) is a brain-derived neurotrophic factor, that has been shown to play an important role in the survival of dopaminergic neurons and the treatment of Parkinson's disease (PD). However, little is known about the role of FGF20 in the treatment of TBI and its underlying mechanism. The purpose of this study was to evaluate the protective effect of recombinant human FGF20 (rhFGF20) on protecting cerebral blood vessels after TBI. In this study, we indicated that rhFGF20 could reduce brain edema, Evans blue penetration and upregulated the expression of blood-brain barrier (BBB)-related tight junction (TJ) proteins, exerting a protective effect on the BBB in vivo after TBI. In the TBI repair phase, rhFGF20 promoted angiogenesis, neurological and cognitive function recovery. In tumor necrosis factor-α (TNF-α)-induced human brain microvascular endothelial cells (hCMEC/D3), an in vitro BBB disruption model, rhFGF20 reversed the impairment in cell migration and tube formation induced by TNF-α. Moreover, in both the TBI mouse model and the in vitro model, rhFGF20 increased the expression of β-catenin and GSK3β, which are the two key regulators in the Wnt/β-catenin signaling pathway. In addition, the Wnt/β-catenin inhibitor IWR-1-endo significantly reversed the effects of rhFGF20. These results indicate that rhFGF20 may prevent vascular repair and angiogenesis through the Wnt/β-catenin pathway.
脑血管疾病的病理学在创伤性脑损伤（TBI）中通过增加颅内压起着重要作用。成纤维细胞生长因子 20（FGF20）是一种脑源性神经营养因子，已被证明在多巴胺能神经元的存活和帕金森病（PD）的治疗中发挥重要作用。然而，关于 FGF20 在 TBI 治疗中的作用及其潜在机制知之甚少。本研究旨在评估重组人 FGF20（rhFGF20）对 TBI 后保护脑血管的作用。在这项研究中，我们表明 rhFGF20 可以减轻脑水肿、伊文思蓝渗透，并上调血脑屏障（BBB）相关紧密连接（TJ）蛋白的表达，从而在 TBI 后体内发挥对 BBB 的保护作用。在 TBI 修复阶段，rhFGF20 促进了血管生成、神经和认知功能的恢复。在肿瘤坏死因子-α（TNF-α）诱导的人脑微血管内皮细胞（hCMEC/D3）体外 BBB 破坏模型中，rhFGF20 逆转了 TNF-α诱导的细胞迁移和管形成损伤。此外，在 TBI 小鼠模型和体外模型中，rhFGF20 增加了 Wnt/β-catenin 信号通路中两个关键调节因子β-catenin 和 GSK3β 的表达。此外，Wnt/β-catenin 抑制剂 IWR-1-endo 显著逆转了 rhFGF20 的作用。这些结果表明，rhFGF20 可能通过 Wnt/β-catenin 通路防止血管修复和血管生成。
