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

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-Cre^ERT2/Igf1r^fl/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-Cre^ERT2/Igf1r^fl/fl) using intravital two-photon microscopy.

Results

In VE-Cadherin-Cre^ERT2/Igf1r^fl/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.