VEGF signalling causes stalls in brain capillaries and reduces cerebral blood flow in Alzheimer's mice.
Brain
; 145(4): 1449-1463, 2022 05 24.
Article
en En
| MEDLINE
| ID: mdl-35048960
ABSTRACT
Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow and exacerbates short-term memory loss in multiple mouse models of Alzheimer's disease. Here, we report that vascular endothelial growth factor (VEGF) signalling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood-brain barrier hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall endothelial nitric oxide synthase protein concentrations, increased occludin levels and decreased the penetration of circulating Evans Blue dye across the blood-brain barrier into the brain parenchyma, suggesting increased blood-brain barrier integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signalling in APP/PS1 mice contributes to aberrant endothelial nitric oxide synthase /occludin-associated blood-brain barrier permeability, increases the incidence of capillary stalls, and leads to reductions in cerebral blood flow. Reducing leucocyte adhesion by inhibiting luminal VEGF signalling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in Alzheimer's disease patients.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_alzheimer_other_dementias
/
6_mental_health_behavioral_disorders
Asunto principal:
Enfermedad de Alzheimer
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Brain
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos