1. Academic Validation
  2. C-kit controls blood-brain barrier permeability by regulating caveolae-mediated transcytosis after chronic cerebral hypoperfusion

C-kit controls blood-brain barrier permeability by regulating caveolae-mediated transcytosis after chronic cerebral hypoperfusion

  • Biomed Pharmacother. 2023 Dec 22:170:115778. doi: 10.1016/j.biopha.2023.115778.
Junkui Shang 1 Wei Li 1 Huiwen Zhang 1 Wan Wang 1 Ning Liu 1 Dandan Gao 2 Fengyu Wang 1 Xi Yan 1 Chenhao Gao 1 Ruihua Sun 1 Haohan Zhang 1 Kai Ma 1 Fengmin Shao 3 Jiewen Zhang 4
Affiliations

Affiliations

  • 1 Department of Neurology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
  • 2 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430072, China.
  • 3 Department of Neurology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China; Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China. Electronic address: shaofengmin@yeah.net.
  • 4 Department of Neurology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China. Electronic address: zhangjiewen@zzu.edu.cn.
Abstract

Blood-brain barrier (BBB) dysfunction plays a pivotal role in the pathology of chronic cerebral hypoperfusion (CCH)-related neurodegenerative diseases. Continuous endothelial cells (EC) that line the blood vessels of the brain are important components of the BBB to strictly control the flow of substances and maintain the homeostatic environment of the brain. However, the molecular mechanisms from the perspective of EC-induced BBB dysfunction after CCH are largely unknown. In this study, the BBB function was assessed using immunostaining and transmission electron microscopy. The EC dysfunction profile was screened by using EC enrichment followed by RNA Sequencing. After identified the key EC dysfunction factor, c-Kit, we used the c-Kit inhibition drug (imatinib) and c-Kit down-regulation method (AAV-BR1-C-kit shRNA) to verify the role of c-Kit on BBB integrity and EC transcytosis after CCH. Furthermore, we also activated c-Kit with stem cell factor (SCF) to observe the effects of c-Kit on BBB following CCH. We explored that macromolecular proteins entered the brain mainly through EC transcytosis after CCH and caused neuronal loss. Additionally, we identified receptor tyrosine kinase c-Kit as a key EC dysfunction molecule. Furthermore, the pharmacological inhibition of c-Kit with imatinib counteracted BBB leakage by reducing caveolae-mediated transcytosis. Moreover, treatment with AAV-BR1-C-kit shRNA, which targets brain EC to inhibit c-Kit expression, also ameliorated BBB leakage by reducing caveolae-mediated transcytosis. Furthermore, the SCF increased the permeability of the BBB by actively increasing caveolae-mediated transcytosis. This study provides evidence that c-Kit is a key BBB permeability regulator through caveolae-mediated transcytosis in EC after CCH.

Keywords

Blood-brain barrier; C-kit; Caveolae-mediated transcytosis; Chronic cerebral hypoperfusion; Endothelial cells.

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