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Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype
GeroScience  (IF7.713),  Pub Date : 2021-08-12, DOI: 10.1007/s11357-021-00405-2
Tarantini, Stefano, Nyúl-Tóth, Ádám, Yabluchanskiy, Andriy, Csipo, Tamas, Mukli, Peter, Balasubramanian, Priya, Ungvari, Anna, Toth, Peter, Benyo, Zoltan, Sonntag, William E., Ungvari, Zoltan, Csiszar, Anna

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.