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-CreERT2/Igf1rf/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-CreERT2/Igf1rf/f mice as
compared to control mice. In VE-Cadherin-CreERT2/Igf1rf/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.
