Insulin regulates neurovascular coupling through astrocytes
Ana M. Fernández, Laura Martinez‐Rachadell, Marta Navarrete, Julia Pose‐Utrilla, José Carlos Dávila, Jaime Pignatelli, Sonia Díaz-Pacheco, Santiago Guerra-Cantera, Emilia Viedma-Moreno, Rocío Palenzuela, Samuel Ruiz de Martı́n Esteban, Ricardo Mostany, Cristina García‐Cáceres, Matthias H. Tschöp, Teresa Iglesias, Marı́a L. de Ceballos, Antonia Gutiérrez, Ignacio Torres‐Alemán
Abstract
Mice with insulin receptor (IR)–deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N -acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.