IGF‐1 Deficiency Promotes Neurovascular Uncoupling: Implications for Cerebromicrovascular Aging and Age‐Related Cognitive Decline

Abstract

Aging is associated with marked deficiency in circulating IGF-1, which was shown to importantly contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling (NVC) is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, we compared NVC in IGF-1 deficient (Igf f/f-TBG-iCre-AAV8) and control mice. We found that glutamate (Glu)-dependent CBF responses to whisker stimulation were significantly decreased in IGF-1 deficient mice. IGF-1 deficiency did not affect neuronal activity-induced cerebral Glu release. Expression of Glu receptors (Grin1, Grin2A, Grm2, Grm4, Grm5) was down-regulated in astrocytes isolated from IGF-1 deficient mice. Glu-stimulated release of astrocyte-derived vasodilator arachidonic acid metabolites (EETs) and EET-dependent CBF responses elicited by whisker stimulation were significantly decreased in IGF-1 deficient mice. IGF-1 deficiency also increased production of the vasoconstrictor 20-HETE. Collectively, IGF-1 deficiency promotes neurovascular uncoupling mimicking the aging phenotype, which is likely causally linked to cognitive impairment.