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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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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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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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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DOI: https://doi.org/10.1038/s41380-022-01618-3
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