ReviewThe American journal of pathology2021
Endothelial Nitric Oxide Synthase-Deficient Mice: A Model of Spontaneous Cerebral Small-Vessel Disease.
Review in The American journal of pathology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk.Frontiers in aging neuroscience · 2022Pooled it
- Biomarker advancements in cerebral small vessel disease: An overview.Neural regeneration research · 2026Article
- Brain endothelial GαEBioMedicine · 2026Article
- A Novel Role for the Small Molecule Cinnamaldehyde in Protecting AgainstAntioxidants (Basel, Switzerland) · 2026Article
- Endothelial TRIM47 regulates blood-brain barrier integrity and cognition via the KEAP1/NRF2 signalling pathway in mice.Communications biology · 2026Article
- The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling.Nature neuroscience · 2026Article
- Neuroinflammation and blood-brain barrier dysfunction in cerebral small vessel disease: mechanisms, biomarkers, and therapeutic implications.European journal of medical research · 2026Review
- Mild traumatic brain injury promotes chronic cerebrovascular inflammation and glymphatic suppression.Molecular neurodegeneration advances · 2026Article
- Primary Cilia and Cardiovascular Risk Factors in Alzheimer's Disease.Brain sciences · 2025Review
- Identification and Characterization of a Translational Mouse Model for Blood-Brain Barrier Leakage in Cerebral Small Vessel Disease.International journal of molecular sciences · 2025Article
- The pathogenesis of cerebral small vessel disease and vascular cognitive impairment.Physiological reviews · 2025Review
- Endothelial cells as key players in cerebral small vessel disease.Nature reviews. Neuroscience · 2025Review
- Roles of neuroimaging markers and biomarkers in cerebral small vessel disease and their associations with cognitive function.Frontiers in neurology · 2025Review
- Review
- Chronic stress in adulthood results in microvascular dysfunction and subsequent depressive-like behavior.Scientific reports · 2024Article
- The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow.International journal of molecular sciences · 2024Review
- Review
- Cerebrovascular Endothelial Dysfunction: Role of BACE1.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
- Article
- MYPT1Translational stroke research · 2024Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)-deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation.
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