Selective disruption of IGF‐1 signaling in astrocytes up‐regulates soluble epoxide hydrolase and impairs EET‐mediated vasodilation

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. To test the hypothesis, that disruption of IGF‐1 signaling specifically in astrocytes impairs pathways involved in regulation of cerebral blood flow regulation 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 epoxyeicosatrienoic acid (EET) synthesis (MS‐PPOH) (4±1%). In contrast, NVC responses in Igfr1f/fGfap‐Cre were unaffected by MS‐PPOH. Analysis of expression of genes enriched in astrocytes that have function al relevance for CBF regulation revealed that in Igfr1f/fGfap‐Cre mice expression of soluble epoxy hydrolase was up‐regulated both at the mRNA and protein level. Pharmacological inhibition of soluble epoxy hydrolase improved NVC responses in Igfr1f/fGfap‐Cre mice. 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 increased degradation of EETs. impairing functional hyperemia. We propose that these findings have relevance for the pathogenesis of cognitive decline associated with age‐related IGF‐1 deficiency.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.