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Reduced endothelial TAK1 impairs vascular integrity in cerebral small vessel disease via the RIPK1-MLKL signalling
Jing Yang1,2,3, Chi Xiao1,2,3, Ming Yi4
1Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Insights
Transforming growth factor-β-activated kinase 1 (TAK1) downregulation in hypertension drives endothelial cell death, impairing the blood-brain barrier and causing cognitive decline. Restoring TAK1 may offer a therapeutic strategy for cerebral small vessel disease.
Area of Science:
- Neuroscience
- Vascular Biology
- Molecular Medicine
Background:
- Hypertension is a key risk factor for cerebral small vessel disease (CSVD), causing blood-brain barrier (BBB) damage and microvascular rarefaction.
- Mechanisms of endothelial cell death and repair in hypertension-related CSVD are not fully understood.
- The role of transforming growth factor-β-activated kinase 1 (TAK1) in cerebrovascular health during hypertension requires further investigation.
Purpose of the Study:
- To investigate the role of TAK1 in hypertension-induced cerebral endothelial cell death and CSVD pathogenesis.
- To elucidate the molecular mechanisms linking TAK1 to cerebrovascular dysfunction and cognitive deficits.
- To evaluate TAK1 as a potential therapeutic target for hypertension-related CSVD.
Main Methods:
- Utilized stroke-prone renovascular hypertensive rats (RHRSP) as a CSVD model.
- Analyzed cerebrovascular integrity, endothelial cell death patterns (necroptosis vs. apoptosis), and TAK1 expression.
- Employed adeno-associated virus (AAV) vectors for brain endothelial-specific TAK1 knockdown or overexpression, validated in vitro.
Main Results:
- Hypertension in RHRSP led to increased endothelial necroptosis and reduced TAK1 expression.
- TAK1 downregulation triggered endothelial necroptosis, tight junction protein loss, microvascular rarefaction, BBB leakage, and spatial memory deficits.
- This cascade was mediated by the TAK1-dependent regulation of the RIPK1-MLKL pathway.
Conclusions:
- TAK1 downregulation promotes RIPK1-MLKL-mediated necroptosis and tight junction protein loss in endothelial cells.
- This mechanism contributes to cerebrovascular integrity impairment and cognitive decline in hypertension-related CSVD.
- TAK1 represents a potential therapeutic target for preventing and treating hypertension-related CSVD.
Background:
Hypertension stands as a major modifiable risk factor for cerebral small vessel disease (CSVD), driving pathological cerebrovascular rarefaction and blood-brain barrier (BBB) compromise through endothelial dysfunction and death. However, the mechanisms regulating cerebral endothelial cell death and endogenous vascular repair pathways remain incompletely characterised. While transforming growth factor-β-activated kinase 1 (TAK1) is recognised as a central regulator of cell survival and homeostasis across multiple tissues, its cerebrovascular-specific functions in hypertension-related CSVD pathogenesis have not been fully delineated. Methods Stroke-prone renovascular hypertensive rats (RHRSP) were used as a CSVD model. Cerebrovascular integrity, endothelial death patterns and TAK1 expression were comparatively analysed between RHRSP and sham-operated controls. Dual-route administration (intracerebroventricular and intravenous) of adeno-associated virus (AAV) vectors (AAV-siTAK1 or AAV-TAK1) was employed to achieve brain endothelial-specific TAK1 knockdown or overexpression. The underlying mechanism was validated in vitro.
Results:
In RHRSP, chronic hypertension induces predominant necroptosis over apoptosis in cerebral cortical and hippocampal endothelial cells, accompanied by a marked reduction in TAK1 expression. Using genetic and pharmacological approaches, we found that TAK1 downregulation triggers a cascade of pathological events: endothelial necroptosis, tight junction protein degradation, irreversible microvascular rarefaction, BBB leakage and spatial memory deficits. Mechanistically, this cascade is centrally mediated by TAK1-dependent regulation of the receptor-interacting protein kinase 1 (RIPK1)-mixed lineage kinase domain-like (MLKL) axis.
Conclusions:
Our results demonstrate that TAK1 downregulation in endothelial cells induces RIPK1-MLKL-mediated necroptosis and downregulation of tight junction protein expression. This coordinated mechanism orchestrates cerebrovascular integrity impairment and subsequent cognitive deterioration. This study positions TAK1 as a promising and potential therapeutic target for the prevention and treatment of hypertension-related CSVD.
