TIE2 expression in hypertensive ICH and its therapeutic modulation with AKB-9778: Implications for brain vascular health
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 immu...
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Veröffentlicht in: | Experimental neurology 2024-04, Vol.374, p.114685-114685, Article 114685 |
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Sprache: | eng |
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Zusammenfassung: | 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.
•TIE2's role in hypertensive ICH: Key in pathogenesis.•TIE2 affects brain endothelial cells via Rap1/MEK ERK.•AKB-9778 activates TIE2, promising for endothelial therapy.•AKB-9778 with antihypertensives reduces bleeding in ICH mice. |
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ISSN: | 0014-4886 1090-2430 |
DOI: | 10.1016/j.expneurol.2024.114685 |