319 - Neurovascular coupling mediated by neuronal nitric oxide in hippocampus and the redox cycle of ascorbate and nitrite

Abstract

Neurovascular coupling is critical for neuronal integrity and survival as it orchestrates the rapid and transient delivery of bioenergetic substrates by the local vasculature to neighboring cells, according to energy demands imposed by neural activation. Failure in neurovascular coupling, either during aging and disease (Alzheimer´s disease, AD) or following acute hypoxic conditions, compromises brain integrity and functionality. The regulation of neurovascular coupling is under the concerted cooperation of the cells comprising the neurovascular unit. However, the complementary task of identifying modulators of NO activity on neurovascular coupling has remained largely underappreciated. We have come to conjecture that the redox and functional interplay of nitric oxide with ascorbate and nitrite would modulate the functionality of glutamatergic synapses in terms of neurovascular coupling. 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. Given that nitrite increases NO bioavailability and augments cerebral blood flow in hippocampus one may envisage that dietary nitrate via the nitrate:nitrite:NO pathway may help sustaining neurovascular coupling in aging and disease.