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

Molecular Psychiatry volume 27, pages 3822–3832 (2022)Cite this article

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Abstract

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.

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Fig. 1: Vascular endothelial growth factor (VEGF) level is upregulated in patients with major depressive disorder (MDD) and chronic restraint stress (RS) mice.
Fig. 2: Chronic restraint stress (RS) increased blood–brain barrier (BBB) permeability.
Fig. 3: Chronic restraint stress (RS) induced morphological blood–brain barrier (BBB) changes.
Fig. 4: Anti-VEGFR2 treatment suppressed 21 d restraint stress (RS)-induced depression and blood–brain barrier (BBB) dysfunction.
Fig. 5: Effect of DC101 treatment on blood–brain barrier (BBB) ultrastructure.

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Acknowledgements

We thank Dr. M. Sekiguchi for use of the imaging facility. This work was supported by a Grant-in-Aid for Scientific Research C from Japan Society for the Promotion of Science (to HM, 17K01983, 20K07985, to K.Sohya, 16KT0199), a Grant-in-Aid for Young Scientists B (to ST, 19K17102), Funding for research to expedite effective drug discovery by Government, Academia and Private partnership from Japan Agency for Medical Research and Development, AMED (to HK, 19ak0101043h0205, 19ak0101044h0404), and an Intramural Research Grants (30-1 and 3-1) for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry (HK and KH). National Center of Neurology and Psychiatry biobank is partly supported by AMED GAPFREE4 (to KH, 21ak0101151h0002).

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Authors and Affiliations

  1. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan

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

  2. Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan

    Kazunori O’Hashi

  3. Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan

    Kazuhisa Sakai & Noritaka Ichinohe

  4. Department of Psychiatry, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Shinsuke Hidese & Hiroshi Kunugi

  5. Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal Diabetes Research Center, Montreal, QC, H2X 0A9, Canada

    Shingo Nakajima

  6. Faculty of Veterinary Medical Science, Okayama University of Science, 1-1 Ridaicho, Kita-ku, Okayama-shi, Okayama, 700-0005, Japan

    Shuichi Chiba

  7. Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Aya Yoshimura

  8. Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan

    Shintaro Ogawa

  9. Division of Physiology, Faculty of Medicine, Saga University, Saga, 849-8501, Japan

    Kazuhiro Sohya

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  1. Hitomi Matsuno
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  2. Shoko Tsuchimine
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Contributions

Conceptualization and writing draft, HM, ST, KO, HK, and K.Sohya; Investigation, HM, ST, KO, K.Sakai, KH, SH, SN, SC, AY, NF, MK, MT, SO, NI, and K.Sohya; Analysis, HM, ST, KO, KH, SH, SN, SC, and AY; Funding acquisition, HM, ST, HK, and K.Sohya. All the authors read and commented on the manuscript.

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Correspondence to Hitomi Matsuno or Kazuhiro Sohya.

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Matsuno, H., Tsuchimine, S., O’Hashi, K. et al. Association between vascular endothelial growth factor-mediated blood–brain barrier dysfunction and stress-induced depression. Mol Psychiatry 27, 3822–3832 (2022). https://doi.org/10.1038/s41380-022-01618-3

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