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Updated: Aug 27, 2025
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Published on: January 3, 2025
Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury
Xiaohao Zhang1, Pengyu Gong2, Ying Zhao3
1Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China; Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China; Department of Neurology, Jiangsu Provincial Second Chinese Medicine Hospital, Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, China.
Background:
Thrombo-inflammation is an important checkpoint that orchestrates infarct development in ischemic stroke. However, the underlying mechanism remains largely unknown. Here, we explored the role of endothelial Caveolin-1 (Cav-1) in cerebral thrombo-inflammation.
Methods:
The correlation between serum Cav-1 level and clinical outcome was analyzed in acute ischemic stroke patients with successful recanalization. Genetic manipulations by endothelial-specific adeno-associated virus (AAV) and siRNA were applied to investigate the effects of Cav-1 in thrombo-inflammation in a transient middle cerebral artery occlusion (tMCAO) model. Thrombo-inflammation was analyzed by microthrombosis formation, myeloid cell infiltration, and endothelial expression of adhesion molecules as well as inflammatory factors.
Findings:
Reduced circulating Cav-1, with the potential to predict microembolic signals, was more frequently detected in recanalized stroke patients without early neurological improvement. At 24 h after tMCAO, serum Cav-1 was consistently reduced in mice. Endothelial Cav-1 was decreased in the peri-infarct region. Cav-1-/- endothelium, with prominent barrier disruption, displayed extensive microthrombosis, accompanied by increased myeloid cell inflammatory infiltration after tMCAO. Specific enhanced expression of endothelial Cav-1 by AAV-Tie1-Cav-1 remarkably reduced infarct volume, attenuated vascular hyper-permeability and alleviated thrombo-inflammation in both wild-type and Cav-1-/- tMCAO mice. Transcriptome analysis after tMCAO further designated Rxrg as the most significantly changed molecule resulting from the knockdown of Cav-1. Supplementation of RXR-γ siRNA reversed AAV-Tie1-Cav-1-induced amelioration of thrombo-inflammation without affecting endothelial tight junction.
Interpretation:
Endothelial Cav-1/RXR-γ may regulate infarct volume and neurological impairment, possibly through selectively controlling thrombo-inflammation coupling, in cerebral ischemia/reperfusion.
Funding:
This work was supported by National Natural Science Foundation of China.
