Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling
Open accessAbstract
Pericytes regulate key neurovascular functions of the brain. Studies in pericyte-deficient transgenic mice with aberrant signaling between endothelial-derived platelet-derived growth factor BB (PDGF-BB) and platelet-derived growth factor receptor β (PDGFRβ) in pericytes have contributed to better understanding of the role of pericytes in the brain. Here, we studied PdgfrβF7/F7 mice, which carry seven point mutations that disrupt PDGFRβ signaling causing loss of pericytes and vascular smooth muscle cells (VSMCs) in the developing brain. We asked whether these mice have a stable or progressive vascular phenotype after birth, and whether both pericyte and VSMCs populations are affected in the adult brain. We found an early and progressive region-dependent loss of brain pericytes, microvascular reductions and blood-brain barrier (BBB) breakdown, which were more pronounced in the cortex, hippocampus and striatum than in the thalamus, whereas VSMCs population remained unaffected at the time when pericyte loss was already established. For example, compared to age-matched controls, PdgfrβF7/F7 mice between 4-6 and 36-48 weeks of age developed a region-dependent loss in pericyte coverage (22-46, 24-44 and 4-31%) and cell numbers (36-49, 34-64 and 11-36%), reduction in capillary length (20-39, 13-46 and 1-30%), and an increase in extravascular fibrinogen-derived deposits (3.4-5.2, 2.8-4.1 and 0-3.6-fold) demonstrating BBB breakdown in the cortex, hippocampus and thalamus, respectively. Capillary reductions and BBB breakdown correlated with loss of pericyte coverage. Our data suggest that PdgfrβF7/F7 mice develop an aggressive and rapid vascular phenotype without appreciable early involvement of VSMCs, therefore providing a valuable model to study regional effects of pericyte loss on brain vascular and neuronal functions. This model could be a useful tool for future studies directed at understanding the role of pericytes in the pathogenesis of neurological disorders associated with pericyte loss such as vascular dementia, Alzheimer's disease, amyotrophic lateral sclerosis, stroke and human immunodeficiency virus-associated neurocognitive disorder.
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Pericyte-deficient mouse models caused by aberrant PDGF-BB/PDGFRβ signaling exhibit impaired BBB formation and maintenance.
“Pericytedeficient mouse models caused by aberrant PDGF-BB/ PDGFR𝛃 signaling (365, 419, 436, 570, 575) exhibit impaired BBB formation (28, 59, 130) and maintenance (59, 436).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [436]
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“80% reduction in pericyte coverage) where PDGF-B binding to heparan sulfate proteoglycans is disrupted and PDGFRβF7/F7 mice which have approximately 40% of the pericytes coverage of control littermates, have elucidated the impact that loss of pericytes has on the BBB (Lindblom et al., 2003; Armulik et al., 2010; Danem…”
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- Authors
- Nikolakopoulou, A. M., Zhao, Z., Montagne, A., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-04-25
- Volume
- 12
- Issue
- 4
- Pages
- e0176225
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5404855
- OpenAlex
- W2607556181
- Cited by
- 109
- References
- 44
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 10 · 2022: 17 · 2021: 13 · 2020: 11 · 2019: 14 · 2018: 12 · 2017: 1
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (AG039452, AG023084, NS034467, NS100459)
- 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 › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- brain pericytes, vascular smooth muscle cells, PDGFRβ signaling, PDGF-BB, pericyte loss, blood-brain barrier disruption, cerebral microvasculature, neurovascular unit
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Mice, Transgenic, Muscle, Smooth, Vascular, Signal Transduction, Pericytes, Receptor, Platelet-Derived Growth Factor beta, Myocytes, Smooth Muscle, Mice
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