Fernandez, Ana MMartinez-Rachadell, LauraNavarrete, MartaPose-Utrilla, JuliaDavila, Jose CarlosPignatelli, JaimeDiaz-Pacheco, SoniaGuerra-Cantera, SantiagoViedma-Moreno, EmiliaPalenzuela, RocioRuiz de Martin Esteban, SamuelMostany, RicardoGarcia-Caceres, CristinaTschöp, MatthiasIglesias, Teresade Ceballos, Maria LGutierrez, AntoniaTorres Aleman, Ignacio2024-02-272024-02-272022-07-14http://hdl.handle.net/10668/19668http://hdl.handle.net/20.500.12105/18710Mice 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/astrocytesinsulinneurovascular couplingAnimalsAstrocytesBrainGlial Fibrillary Acidic ProteinGlucoseInsulinMiceMice, KnockoutNeovascularization, PhysiologicNeurovascular CouplingReactive Oxygen SpeciesReceptor, InsulinVascular Endothelial Growth Factor AAttribution-NonCommercial-NoDerivatives 4.0 International3585832511929e220452711910.1073/pnas.22045271191091-6490Proceedings of the National Academy of Sciences of the United States of Americaopen access