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

• Published in: GeroScience Vol. 43; no. 5; pp. 2387 - 2394
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-10-2021; Springer Nature B.V
• Subjects: Aging; Animals; Biomedical and Life Sciences; Blood flow; Brain - metabolism; Brain - physiopathology; Cadherins; Cell Biology; Cerebral blood flow; Cognitive ability; Cortex (barrel); Endothelial Cells; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Geriatrics/Gerontology; Hyperemia; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Life Sciences; Mice; Microvasculature; Mimicry; Molecular Medicine; Neuroimaging; Neurovascular Coupling; NG-Nitroarginine methyl ester; Nitric-oxide synthase; Original; Original Article; Phenotype; Phenotypes; Receptor, IGF Type 1 - genetics; Somatosensory cortex; Neurovascular Aging; Functional hyperemia; Vascular cognitive impairment; Neurovascular uncoupling; Ageing; IGF-1; Cerebrovascular; Neurovascular unit; Insulin-like growth factor 1; VCI
• ISSN: 2509-2715; 2509-2723
• DOI: 10.1007/s11357-021-00405-2

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.