Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow

Abstract

The brain has impressive energy requirements and paradoxically, very limited energy reserves, implying its huge dependency on continuous blood supply. Aditionally, cerebral blood flow must be dynamically regulated to the areas of increased neuronal activity and thus, of increased metabolic demands. The coupling between neuronal activity and cerebral blood flow (CBF) is supported by a mechanism called neurovascular coupling (NVC). Among the several vasoactive molecules released by glutamatergic activation, nitric oxide (•NO) is recognized to be a key player in the process and essential for the development of the neurovascular response. Classically, •NO is produced in neurons upon the activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor by the neuronal isoform of nitric oxide synthase and promotes vasodilation by activating soluble guanylate cyclase in the smooth muscle cells of the adjacent arterioles. This pathway is part of a more complex network in which other molecular and cellular intervenients, as well as other sources of •NO, are involved. The elucidation of these interacting mechanisms is fundamental in understanding how the brain manages its energy requirements and how the failure of this process translates into neuronal dysfunction. Here, we aimed to provide an integrated and updated perspective of the role of •NO in the NVC, incorporating the most recent evidence that reinforces its central role in the process from both viewpoints, as a physiological mediator and a pathological stressor. First, we described the glutamate-NMDA receptor-nNOS axis as a central pathway in NVC, then we reviewed the link between the derailment of the NVC and neuronal dysfunction associated with neurodegeneration (with a focus on Alzheimer’s disease). We further discussed the role of oxidative stress in the NVC dysfunction, specifically by decreasing the •NO bioavailability and diverting its bioactivity toward cytotoxicity. Finally, we highlighted some strategies targeting the rescue or maintenance of •NO bioavailability that could be explored to mitigate the NVC dysfunction associated with neurodegenerative conditions. In line with this, the potential modulatory effects of dietary nitrate and polyphenols on •NO-dependent NVC, in association with physical exercise, may be used as effective non-pharmacological strategies to promote the •NO bioavailability and to manage NVC dysfunction in neuropathological conditions.

Nitric oxide signaling in health and disease

“…The physiological mechanism that couples nutritional blood flow to brain neuronal activity and metabolism is termed neurovascular coupling (NVC). Full mechanistic insight into how NVC works is still lacking, but experimental data strongly indicate that NO is a key intermediate mediator (Lourenc ¸o and Laranjinha, 2021). Although other substances are involved such as prostanoids, purines, and K + , experiments using NOS inhibition reduce the NVC response by approximately 60% (Hosford and Gourine, 2019).…”

Monitoring of cerebrovascular pressure reactivity in children may predict neurologic outcome after hypoxic-ischemic brain injury

“…Despite the multitude of CAR data, autoregulation still cannot be equated with cerebral blood flow regulation. Other mechanisms such as neurovascular coupling, carbon dioxide-induced vascular reactivity, myocardial function, autonomic nervous system control and the role of the neurovascular unit have to be considered [ 21 ]. Targeted neuroprotective agents are not yet available [ 22 ] though promising experimental data is available [ 23 , 24 ].…”

Nitric oxide is not responsible for the initial sensory-induced neurovascular coupling response in mouse cortex

“…CBF deficits are observed early in AD (Iturria-Medina et al, 2016) and are linked to cognitive decline (Hays et al, 2016; Leijenaar et al, 2017). Therefore, targeting nNOS INs, or increasing NO bioavailability (Lourenço and Laranjinha, 2021), to reverse CBF deficits may prove to be a beneficial strategy for preventing cognitive decline.…”