Selective disruption of IGF‐1 signaling in astrocytes impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

Abstract

Insulin‐like growth factor 1 (IGF‐1) exerts multifaceted protective effects on the cerebral microcirculation and age‐related reduction of circulating IGF‐1 levels is known to promote cognitive decline. Astrocyte‐mediated neurovascular coupling (NVC), which adjusts cerebral blood flow to increased energy requirements of activated neurons, plays a critical role in the maintenance of normal neuronal function. Although previous studies demonstrate that circulating IGF‐1 deficiency significantly impairs NVC, the role of astrocyte‐specific effects of IGF‐1 in regulation of NVC is not completely understood. On the basis of previous findings we hypothesized that disruption of IGF‐1 signaling specifically in astrocytes impairs NVC responses mediated by epoxyeicosatrienoic acids (EETs). To test this hypothesis, we assessed changes in local cerebral blood flow elicited by contralateral whisker stimulation in mice with astrocyte‐specific knock‐down of IGF‐1 receptor 1 (Igfr1f/fGfap‐Cre), and respective controls using laser speckle contrast imaging. We found that NVC responses were significantly impaired in Igfr1f/fGfap‐Cre mice (4±1%) as compared to that in control mice (10±1%). In control mice NVC responses were significantly decreased by pharmacological inhibition of EETs synthesis (MS‐PPOH) (4±1%). In contrast, NVC responses in Igfr1f/fGfap‐Cre were unaffected by MS‐PPOH. Collectively, our findings support the concept that normal astrocyte function is essential for the adequate NVC responses and provide evidence that decreased IGF‐1 input to astrocytes results in impaired EET mediation of NVC responses, which may contribute to cognitive decline associated with age‐related IGF‐1 deficiency.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on AgingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.