Abstract
The functional connection of glutamate receptors with nNOS in neurons contributes to the coupling between neuronal activation and changes in local cerebral blood flow, i.e., the neurovascular coupling. Failure in neurovascular coupling, either during aging and disease (Alzheimer´s disease, AD) or following acute hypoxic conditions, compromises brain integrity and functionality. Hypoxia may compromise the coupling by mechanisms that include a deficient synthesis of NO, for which O2 is a substrate. By using a multimodal approach to probe the dynamics of NO, ascorbate and cerebral blood flow in vivo in hippocampus of Wistar and Fisher 344 rats and of a triple transgenic mice model of AD we support that (1) neuronal-derived NO acts as a direct mediator of neurovascular coupling, (2) upon glutamatergic stimulation, volume signaling by NO is an intrinsically controlled mechanism due to increased blood flow, (3) neurovascular coupling is impaired in AD and aging due to vascular dysfunction, (4) under acidic/hypoxic conditions, nitrite is reduced by ascorbate to NO and (5) the redox interaction of nitrite/ascorbate/NO contributes to neurovascular coupling. The results support that dietary nitrate might modulate neurovascular coupling in aging and disease via the nitrate:nitrite:NO pathway.
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