Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury

Xiaohao Zhang; Pengyu Gong; Ying Zhao; Ting Wan; Kang Yuan; Yunyun Xiong; Min Wu; Mingming Zha; Yunzi Li; Teng Jiang; Xinfeng Liu; Ruidong Ye; Yi Xie; Gelin Xu

doi:10.1016/j.ebiom.2022.104275

Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury

EBioMedicine. 2022 Oct:84:104275. doi: 10.1016/j.ebiom.2022.104275. Epub 2022 Sep 21.

Authors

Xiaohao Zhang¹, Pengyu Gong², Ying Zhao³, Ting Wan³, Kang Yuan³, Yunyun Xiong⁴, Min Wu⁵, Mingming Zha³, Yunzi Li³, Teng Jiang⁶, Xinfeng Liu³, Ruidong Ye³, Yi Xie⁷, Gelin Xu⁸

Affiliations

¹ Department 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.
² Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226000, China.
³ Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China.
⁴ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing 100070, China; Chinese Institute for Brain Research, Beijing 100070, China.
⁵ Department of Neurology, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China.
⁶ Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China.
⁷ Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China. Electronic address: xy_307@126.com.
⁸ Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China. Electronic address: gelinxu@nju.edu.cn.

Abstract

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.

Keywords: Caveolin-1; Inflammation; Ischemic stroke; Microthrombosis; Vascular endothelium.

MeSH terms

Animals
Caveolin 1 / genetics
Caveolin 1 / metabolism
Endothelium / metabolism
Infarction, Middle Cerebral Artery / genetics
Infarction, Middle Cerebral Artery / metabolism
Inflammation / genetics
Inflammation / metabolism
Ischemic Stroke* / genetics
Ischemic Stroke* / therapy
Mice
RNA, Small Interfering
Reperfusion Injury* / genetics
Reperfusion Injury* / metabolism
Thrombosis*

Substances

Caveolin 1
RNA, Small Interfering