Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression
Open accessAbstract
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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SGK1 plays a critical role in VEGF-mediated angiogenesis, which plays a role in both stress-induced BBB dysfunction and development of depressive-like behaviors.
“This finding underscores the critical role of SGK1 in VEGF-mediated angiogenesis, which plays a role in both stress-induced BBB dysfunction and the development of depressive-like behaviors”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Matsuno et al., 2022
The Abstract reports that VEGF/VEGFR2 contributes to stress-induced BBB permeability and depressive-like behavior in chronically stressed mice, and describes VEGF as a mediator of angiogenesis. It does not mention SGK1 or establish that SGK1 is critical to VEGF-mediated angiogenesis; nor does it show that angiogenesis itself causes the reported BBB and behavioral effects. (LLM, conf=0.88)
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Cites
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Depression in Alzheimer’s Disease: Epidemiology, Mechanisms, and Treatment
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Blood brain barrier and inflammation in depression
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Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
Patel, S., Govindarajan, V., Chakravarty, S., & Dubey, N. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113326 · Cited by 10 · see citing works
- Authors
- Matsuno, H., Tsuchimine, S., O’Hashi, K., Sakai, K., Hattori, K., Hidese, S., Nakajima, S., Chiba, S., Yoshimura, A., Fukuzato, N., Kando, M., Tatsumi, M., Ogawa, S., Ichinohe, N., Kunugi, H., & Sohya, K.
- Affiliations
- National Center of Neurology and Psychiatry (JP)
- Nihon University (JP)
- Okayama University of Science (JP)
- Fujita Health University (JP)
- Saga University (JP)
- Corresponding author
- Matsuno, Hitomi
- Sohya, Kazuhiro
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2022-05-26
- Volume
- 27
- Issue
- 9
- Pages
- 3822-3832
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W4281550041
- Cited by
- 164
- References
- 14
- Citations by year
- 2026: 38 · 2025: 53 · 2024: 38 · 2023: 30 · 2022: 5
- FWCI
- 11.06
- Type
- journal article
- Language
- en
- Open access
- green
- pure.teikyo.jp
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- MEXT | Japan Society for the Promotion of Science (17K01983, 20K07985, 19K17102, 16KT0199)
- Japan Agency for Medical Research and Development (19ak0101043h0205, 19ak0101044h0404)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- vascular endothelial growth factor, VEGFR2, blood-brain barrier permeability, chronic restraint stress, stress-induced depression, major depressive disorder, neurovascular dysfunction, brain endothelial cells, anhedonia
- MeSH terms
- Animals, Blood-Brain Barrier, Brain Diseases, Capillary Permeability, Depression, Depressive Disorder, Major, Major Depressive Disorder, Mice, Inbred BALB C, Vascular Endothelial Growth Factor A, Endothelial Cells, Mice
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