Cerebral venous outflow disturbance exacerbates ischemic stroke via an endothelium-initiated inflammatory cascade: an integrated single-cell transcriptomic analysis.

BACKGROUND

Unfavorable cerebral venous outflow (VO) critically worsens ischemic stroke (IS) prognosis, yet the underlying cellular mechanisms driving this aggravation remain obscure. This study aimed to explore the impact of VO disturbance on ischemic brain injury.

METHODS

We superimposed the left internal jugular vein occlusion (LIJVO) onto a rat model of ischemia/reperfusion (I/R). Key pathological indices were assessed and the transcriptomic landscape of the injury using the integrated single-cell and single-nucleus RNA sequencing approach, followed by immunofluorescence validation.

RESULTS

Superimposed LIJVO significantly exacerbated neurological deficits and infarction, precipitating malignant brain edema and blood-brain barrier breakdown (P < 0.05). The pathological expansion of pro-inflammatory Endothelial0 and Microglia1 subpopulations were identified. We traced these deteriorations to an endothelial-initiated inflammatory cascade: a specific Endothelial0 emerged to recruit leukocytes and trigger a feed-forward loop with hyper-reactive Microglia1. This crosstalk may drive a cytokine storm and tight junction collapse, ultimately leading to severe perivascular infiltration and accelerated neuronal injury.

CONCLUSION

Collectively, this study elucidates that unfavorable VO functions as a critical aggravator in IS via an endothelial-initiated inflammatory cascade. Targeting upstream endothelial activation represents a promising therapeutic strategy for the IS patients with compromised venous drainage.