{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China",
        "Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, Guangdong, China",
        "National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China"
      ],
      "name": "Jing Yang"
    },
    {
      "affiliations": [
        "Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China",
        "Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, Guangdong, China",
        "National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China"
      ],
      "name": "Chi Xiao"
    },
    {
      "affiliations": [
        "Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China"
      ],
      "name": "Ming Yi"
    },
    {
      "affiliations": [
        "Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China",
        "Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, Guangdong, China",
        "National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China"
      ],
      "name": "Kun Zhou"
    },
    {
      "affiliations": [
        "Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Xiangming Xu"
    },
    {
      "affiliations": [
        "Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China",
        "Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, Guangdong, China",
        "National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China"
      ],
      "name": "Yuhua Fan"
    }
  ],
  "title": "Reduced endothelial TAK1 impairs vascular integrity in cerebral small vessel disease via the RIPK1-MLKL signalling pathway",
  "uid": "b5b6523f-31b2-5a7b-891e-b8f690583425"
}