Association between vascular endothelial growth factor-mediated blood–brain barrier dysfunction and stress-induced depression

Hitomi Matsuno, Shoko Tsuchimine, Kazunori O’Hashi, Kazuhisa Sakai, Kotaro Hattori, Shinsuke Hidese, Shingo Nakajima, Shuichi Chiba, Aya Yoshimura, Noriko Fukuzato, Mayumi Kando, Megumi Tatsumi, Shintaro Ogawa, Noritaka Ichinohe, Hiroshi Kunugi, Kazuhiro Sohya

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood–brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.

Original languageEnglish
Pages (from-to)3822-3832
Number of pages11
JournalMolecular Psychiatry
Issue number9
Publication statusPublished - 09-2022

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


Dive into the research topics of 'Association between vascular endothelial growth factor-mediated blood–brain barrier dysfunction and stress-induced depression'. Together they form a unique fingerprint.

Cite this