Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype

Age-related impairment of neurovascular coupling (NVC; or functional hyperemia) compromises moment-to-moment adjustment of regional cerebral blood flow to increased neuronal activity and thereby contributes to the pathogenesis of vascular cognitive impairment (VCI). Previous studies established a causal link among age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), neurovascular dysfunction and cognitive impairment. Endothelium-mediated microvascular dilation plays a central role in NVC responses. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, endothelium-mediated NVC responses were studied in a novel mouse model of accelerated neurovascular aging: mice with endothelium-specific knockout of IGF1R (VE-Cadherin-Cre(ERT2)/Igf1r(f/f)). Increases in cerebral blood flow in the somatosensory whisker barrel cortex (assessed using laser speckle contrast imaging through a cranial window) in response to contralateral whisker stimulation were significantly attenuated in VE-Cadherin-Cre(ERT2)/Igf1r(f/f) mice as compared to control mice. In VE-Cadherin-Cre(ERT2)/Igf1r(f/f) mice, the effects of the NO synthase inhibitor L-NAME were significantly decreased, suggesting that endothelium-specific disruption of IGF1R signaling impairs the endothelial NO-dependent component of NVC responses. Collectively, these findings provide additional evidence that IGF-1 is critical for cerebromicrovascular endothelial health and maintenance of normal NVC responses.

Automated summary

The impairment of neurovascular coupling plays a role in the pathogenesis of vascular cognitive impairment, with endothelium-mediated microvascular dilation being central to NVC responses. Disruption of endothelial IGF1R signaling leads to decreased nitric oxide-dependent component of NVC responses, highlighting the importance of IGF-1 in maintaining normal cerebromicrovascular endothelial health.