下调和上调
MAPK/ERK通路
血管生成
受体酪氨酸激酶
血管生成素受体
医学
神经科学
脑出血
药理学
信号转导
癌症研究
细胞生物学
生物
受体
内科学
基因
蛛网膜下腔出血
生物化学
作者
Jingkun Wu,Hongbin Wang,Naizhu Wang,Zai Wang,Qinsheng Zhu
标识
DOI:10.1016/j.expneurol.2024.114685
摘要
Hypertensive intracerebral hemorrhage (ICH) is a devastating condition, the molecular underpinnings of which remain not fully understood. By leveraging high-throughput transcriptome sequencing and network pharmacology analysis, this study unveils the significant role of the tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) in ICH pathogenesis. Compared to controls, a conspicuous downregulation of TIE2 was observed in the cerebral blood vessels of hypertensive ICH mice. In vitro assays with human brain microvascular endothelial cells (HBMEC), HBEC-5i revealed that modulation of TIE2 expression significantly influences cellular proliferation, migration, and angiogenesis, mediated via the Rap1/MEK/ERK signaling pathway. Notably, the small molecule AKB-9778 was identified to target and activate TIE2, affecting the functional attributes of HBEC-5i. In vivo experiments further demonstrated that combining AKB-9778 with antihypertensive drugs could mitigate the incidence and volume of bleeding in hypertensive ICH mouse models, suggesting potential therapeutic implications.
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