Endothelial deficiency of insulin-like growth factor-1 receptor leads to blood-brain barrier disruption and accelerated endothelial senescence in mice, mimicking aspects of the brain aging phenotype.
Microcirculation
; 31(2): e12840, 2024 Feb.
Article
en En
| MEDLINE
| ID: mdl-38082450
ABSTRACT
INTRODUCTION:
Age-related blood-brain barrier (BBB) disruption, cerebromicrovascular senescence, and microvascular rarefaction substantially contribute to the pathogenesis of vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Previous studies established a causal link between age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), cerebromicrovascular dysfunction, and cognitive decline. The aim of our study was to determine the effect of IGF-1 signaling on senescence, BBB permeability, and vascular density in middle-age and old brains.METHODS:
Accelerated endothelial senescence was assessed in senescence reporter mice (VE-Cadherin-CreERT2 /Igf1rfl/fl × p16-3MR) using flow cytometry. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, BBB integrity and capillary density were studied in mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2 /Igf1rfl/fl ) using intravital two-photon microscopy.RESULTS:
In VE-Cadherin-CreERT2 /Igf1rfl/fl mice (1) there was an increased presence of senescent endothelial cells; (2) cumulative permeability of the microvessels to fluorescent tracers of different molecular weights (0.3-40 kDa) is significantly increased, as compared to that of control mice, whereas decline in cortical capillary density does not reach statistical significance.CONCLUSIONS:
These findings support the notion that IGF-1 signaling plays a crucial role in preserving a youthful cerebromicrovascular endothelial phenotype and maintaining the integrity of the BBB.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factor I del Crecimiento Similar a la Insulina
/
Barrera Hematoencefálica
Límite:
Animals
Idioma:
En
Revista:
Microcirculation
Asunto de la revista:
ANGIOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos