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
Rafał Gulej, Boglárka Csík, Janet Faakye, Stefano Tarantini, Santny Shanmugarama, Siva Sai Chandragiri, Péter Mukli, Shannon M. Conley, Anna Csiszár, Zoltán Ungvári, Andriy Yabluchanskiy, Ádám Nyúl‐Tóth
Abstract
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.