How do we kNOw the individual contribution of eNOS and nNOS for cerebral blood flow regulation?

Nitric oxide (NO) is a key signalling molecule in cardiovascular health, and an imbalance between NO production and removal/inactivation is a hallmark of cardiovascular disease. Moreover, impairments to the NO-system have been associated with many neurodegenerative diseases, demonstrating NO's far-reaching role in physiological functions (De Silva & Faraci, 2020). In the brain, neuronal activation increases regional metabolism and requires adequate blood flow to supply the localized metabolic demand – a fine-tune control termed neurovascular coupling. Recently, the ubiquitous molecule NO has been shown to play an essential role in neurovascular coupling in humans when Hoiland et al. (2020) reported that the infusion of a non-selective blocker of NO production reduced the peak neurovascular coupling response by ∼ 30% in young, healthy males. As the brain is a costly metabolic organ with limited oxygen and nutrient storage capacity, several extensive and interrelated mechanisms are required to maintain a sufficient blood flow. The endothelium serves an essential role in producing powerful vasodilators including NO, prostacyclin and endothelial-derived hyperpolarizing factor. These vasoactive compounds regulate cerebral vascular tone both at rest and during homeostatic challenges, such as alterations in blood gases. The recent findings published in The Journal of Physiology by Carter et al. (2021) substantiate NO's role in regulating blood flow to the brain. Carter et al. (2021) investigated the contribution of NO to cerebral blood flow (CBF) during a non-selective blockade of nitric oxide synthase (NOS) NG-monomethyl-l-arginine (l-NMMA) in healthy adult subjects (n = 14; 7/7 females/males). 4D flow and arterial spin labelling magnetic resonance imaging techniques were used for quantifying macrovascular and microvascular cerebrovascular blood flow, respectively. The results show that NOS inhibition by l-NMMA infusion reduced macrovascular by 5–7% and microvascular blood flow by 7–11%. Contrary to what the authors hypothesized, the relative decrease in blood flow in the anterior and posterior areas in the brain was similar after NOS blockade (Carter et al. 2021). That is an interesting finding because previous work suggested region-specific NOS expression and activity in the brain, with a larger contribution of NOS influence in the anterior area of the brain. It is of note that three NOS isoforms are found, the endothelial NOS, neuronal NOS and inducible NOS isoforms (De Silva & Faraci, 2020). Therefore, NO production is not exclusive to endothelial cells as neurons release NO, producing local vasodilatation through glutamate N-methyl d-aspartate receptors (NMDAR) upon increased neuronal activity. To identify the relative contribution of the source of NO responsible for that regulating basal CBF or during neurovascular coupling, selective blockade of neuronal and endothelial NOS would be valuable. A recent study in humans investigated to what extent the neuronal NO isoform regulates global and regional brain blood flow by using a selective blockade of neuronal NO using S-methyl-l-thiocitrulline (SMTC). The findings indicated that SMTC decreased global CBF by ∼4%, with a more noticeable reduction in the right hippocampus, parahippocampal gyrus and medial temporal lobe, key regions responsible for memory formation and spatial cognition (O'Gallagher et al. 2021). Given the methodological differences, it is difficult to draw comparisons between the findings of the two studies and speculate about the individual contribution each NOS isoform has on regulating brain blood flow. However, these findings help us understand the contribution of NO to regulating CBF during basal conditions (Figure 1). However, the brain is constantly cognitively taxed in daily activities. For instance, in a simple task such as walking up stairs or speaking a language, neuronal activity increases in the motor area and the frontal, temporal and parietal cortex, requiring fine-tuned 'neuronal–vascular' interactions regulating CBF under dynamic daily conditions. Therefore, it would be interesting to examine the individual role of endothelial and neuronal NOS inhibition on neurovascular coupling and regional CBF. Work by Hoiland et al. (2020) showed that the reduced neurovascular coupling response was not concomitant with a global CBF reduction even though the peak velocity, conductance and oxygen delivery in the posterior cerebral artery were lower during NOS blockade. Future work is necessary to ascertain whether neurovascular coupling is affected by selective reductions in eNOS versus nNOS as well as how this relates to region-specific NOS expression and activity in the brain. Carter et al. (2021) have provided exciting insights into cerebrovascular regulation by NO and have provided direction for future studies. As such, studies aiming to unravel the mechanisms underlying the impaired regulation of regional brain blood flow and neurovascular coupling in older adults are warranted. Vascular changes in the ageing brain may contribute to a decline in cognitive capacity, memory loss, and an increased risk of developing dementia and Alzheimer's (De Silva & Faraci, 2020). Older adults exhibit reduced NO bioavailability (probably due to a lower formation of NO) and augmented production of reactive oxygen species, which readily react with NO, lowering its bioavailability. The dysfunction of local NO production may jeopardize brain perfusion in basal conditions and when increased blood flow is required, for example with increased neuronal activity-causing neurovascular uncoupling and compromising the brain's performance (De Silva & Faraci, 2020). We propose that the role of NOS for resting cerebrovascular regulation would be attenuated in ageing and, therefore, this would reflect a lower neurovascular coupling response in older individuals. Finally, given the inherent changes in the ageing process, it is questionable whether NO's contribution and its different isoforms regulating global and regional CBF would remain similar to what is observed in young adults. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons listed as authors qualify for authorship. No funding was received for this work.

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