Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System
Open accessAbstract
Objective Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution, and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood-brain barrier function is less well understood. In this report, we explored the impact of the loss of VSMC in the Notch3(-/-) mouse on blood vessel integrity in the central nervous system. Approach and results Notch3(-/-) mice showed focal disruptions of the blood-brain barrier demonstrated by extravasation of tracers accompanied by fibrin deposition in the retinal vasculature. This blood-brain barrier leakage was accompanied by a regionalized and patchy loss of VSMC, with VSMC gaps predominantly in arterial resistance vessels of larger caliber. The loss of VSMC appeared to be caused by progressive degeneration of VSMC resulting in a gradual loss of VSMC marker expression and a progressive acquisition of an aberrant VSMC phenotype closer to the gaps, followed by enhanced apoptosis and cellular disintegration in the gaps. Arterial VSMC were the only mural cell type that was morphologically affected, despite Notch3 also being expressed in pericytes. Transcriptome analysis of isolated brain microvessels revealed gene expression changes in Notch3(-/-) mice consistent with loss of arterial VSMC and presumably secondary transcriptional changes were observed in endothelial genes, which may explain the compromised vascular integrity. Conclusions We demonstrate that…
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Notch3 null mice exhibit BBB disruption shown by leakages of circulating tracers in the brain and perivascular deposits of fibrin.
“Notch3 null mice exhibit BBB disruption shown by leakages of circulating tracers in the brain and perivascular deposits of fibrin (244), suggesting that normal NOTCH function is required for the proper maintenance of the BBB.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [244]
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Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Establishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670 · see citing works
Self-citationPericytes of the neurovascular unit: key functions and signaling pathways
Sweeney, M. D., Ayyadurai, S., & Zlokovic, B. V. (2016) · Nature Neuroscience · doi:10.1038/nn.4288 · Cited by 1,125 · see citing works
- Authors
- Henshall, T. L., Keller, A., He, L., Johansson, B. R., Wallgard, E., Raschperger, E., Mäe, M. A., Jin, S., Betsholtz, C., & Lendahl, U.
- Affiliations
- Uppsala University (SE)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2015-02
- Volume
- 35
- Issue
- 2
- Pages
- 409-420
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2112202992
- Cited by
- 145
- References
- 0
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 17 · 2023: 10 · 2022: 21 · 2021: 15 · 2020: 10 · 2019: 13 · 2018: 11 · 2017: 7 · 2016: 10 · 2015: 5
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.zora.uzh.ch
- Licence
- other-oa
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Ragnar Söderbergs stiftelse
- Fondation Leducq
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (134147)
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Uppsala Universitet
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- Notch3, vascular smooth muscle cells, blood-brain barrier, retinal vasculature, fibrin deposition, apoptosis, pericytes, endothelial gene expression
- MeSH terms
- Receptor, Notch3, Actins, Animals, Blood Vessels, Blood-Brain Barrier, Capillary Permeability, Female, Genotype, Male, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Phenotype, Retinal Vessels, Transcription, Genetic, Signal Transduction, Biomarkers, Apoptosis, Mice, Knockout, Gene Expression Regulation, Developmental, Pericytes, Gene Expression Profiling, Myocytes, Smooth Muscle, Endothelial Cells, Receptors, Notch, Microvessels
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