Astrocyte-derived VEGF increases cerebral microvascular permeability under high salt conditions
Open accessAbstract
Excess salt (NaCl) intake is closely related to a variety of central nervous system (CNS) diseases characterized by increased cerebral microvascular permeability. However, the link between a high salt diet (HSD) and the breakdown of tight junctions (TJs) remains unclear. In the present study, we found that high salt does not directly influence the barrier between endothelial cells, but it suppresses expression of TJ proteins when endothelial cells are co-cultured with astrocytes. This effect is independent of blood pressure, but depends on the astrocyte activation via the NFκB/MMP-9 signaling pathway, resulting in a marked increase in VEGF expression. VEGF, in turn, induces disruption of TJs by inducing phosphorylation and activation of ERK and eNOS. Correspondingly, the HSD-induced disruption of TJ proteins is attenuated by blocking VEGF using the specific monoclonal antibody Bevacizumab. These results reveal a new axis linking a HSD to increased cerebral microvascular permeability through a VEGF-initiated inflammatory response, which may be a potential target for preventing the deleterious effects of HSD on the CNS.
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The breakdown of claudin-5 can be attributed to VEGF-mediated MMP expression.
“several studies in ischaemic stroke, a neurological disease characterized by BBB impairment, suggest that the breakdown of claudin-5 can be attributed to VEGF-mediated matrix metalloproteinase (MMP) expression [52–55].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [54]
The Results (VEGFhi/+ mice; page not provided) report reduced claudin-5 with increased astrocyte-derived VEGF. The Results also report increased MMP-9 under high-salt conditions, but identify ERK/eNOS—not MMP expression—as the pathway examined for VEGF’s effect on tight junctions. The paper does not establish MMP-mediated claudin-5 breakdown in ischaemic stroke. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAstrocytes have been shown to secrete pro-angiogenic growth factors in aging and disease, influencing BBB development, maintenance, and permeability.
“Astrocytes have been shown to secrete each of the above pro-angiogenic growth factors in aging and disease, influencing BBB development, maintenance, and permeability.87,88,89,90”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [87]
The Introduction identifies astrocyte-derived VEGF as a pro-angiogenic factor that increases vascular permeability, and the Discussion reports that it increases cerebral microvascular permeability under high-salt conditions. The Introduction also describes astrocytes’ role in BBB establishment and maintenance, but this paper does not show that secreted VEGF drives those functions or establish the claim specifically in aging. (LLM, conf=0.84)
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Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain
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- Authors
- Deng, Z., Zhou, L., Wang, Y., Liao, S., Huang, Y., Shan, Y., Tan, S., Zeng, Q., Peng, L., Huang, H., & Lu, Z.
- Affiliations
- Sun Yat-sen University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Corresponding author
- Huang, Haiwei
- Lu, Zhengqi
- ORCID
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2020-06-22
- Volume
- 12
- Issue
- 12
- Pages
- 11781-11793
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC7343440
- OpenAlex
- W3036806129
- Cited by
- 34
- References
- 41
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 1 · 2020: 2
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by
- Locations
- Aging (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81671178, 81971166)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- high-salt diet, astrocytes, vascular endothelial growth factor, tight junctions, endothelial cells, ERK1/2 phosphorylation, endothelial nitric oxide synthase, bevacizumab, neuroinflammation, blood-brain barrier
- MeSH terms
- Bevacizumab, Animals, Astrocytes, Blood-Brain Barrier, Capillary Permeability, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular, Humans, Male, Mice, Transgenic, Phosphorylation, Specific Pathogen-Free Organisms, Down-Regulation, NF-kappa B, Sodium Chloride, Dietary, Coculture Techniques, Tight Junctions, Matrix Metalloproteinase 9, MAP Kinase Signaling System, Vascular Endothelial Growth Factor A, Endothelial Cells, Mice, Rats, Nitric Oxide Synthase Type III, Primary Cell Culture, Tight Junction Proteins
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