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.

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