Neurovascular Coupling: Sending This Signal Here, Hope You Pick It Up Loud and Clear

PERSPECTIVES

Because the brain has high metabolic activity but very limited energy reserve, it needs a continual supply of blood to provide O₂ and glucose to support energy demands. As a result, brain function relies on precise regulation of cerebral blood flow (CBF). Normally, CBF varies regionally based on energy consumption. With physiological challenges, changes in CBF occur at regional, segmental, and temporal levels, supporting a continually integrating network of perfusion.

Neurovascular coupling (NVC) can be defined as the functional coupling between activity of neurons and local CBF (Iadecola, 2017). While this definition is deceivingly simple, decades of study have revealed a signaling process with layers of complexity (multiple cell types and mediators, multiple segments of the circulation, etc). Ongoing investigations continue to provide novel insight into mechanistic details of NVC, its impact on brain health, and its clinical implications. The hemodynamic component of NVC is the basis for functional magnetic resonance imaging, used commonly for brain mapping in neuroscience and clinically.

Signaling networks within and between cells are engaged during normal NVC. Mechanisms include neural activation, glutamatergic signaling, production of nitric oxide (NO) and other mediators, with signaling to adjacent cells and dilation of the local vasculature (Faraci & Breese, 1993; Iadecola, 2017). Distal components of the vascular tree – perhaps capillary endothelial cells – act as sensors of neural activity, sending electrical signals to the upstream vasculature, including vessels on the brain surface (pial arteries and arterioles). Because of the known distribution of vascular resistance in the cerebral circulation (Iadecola, 2017), an effective physiological response that maintains microvascular perfusion pressure requires such integration, resulting in dilation of resistance vessels on the pial surface in addition to microvessels deep within the parenchyma.

NVC has been studied in diverse models from across the phylogenetic tree, with representatives from vertebrate classes that include teleosts, birds, and mammals (e.g., rodents, lagomorths, New and Old World monkeys). In the past, mechanistic insight has predominantly been obtained using in vivo animal models or in vitro approaches (e.g., brain slices, isolated vessels). In contrast, there has been relatively little work addressing NVC signaling mechanisms in humans.

The study by Hoiland et al. sought to help fill this gap, taking advantage of the integrated NVC response by measuring blood flow velocity (assumed to be an accurate index of quantitative blood flow per unit time) in the posterior cerebral artery during visual stimulation (Hoiland et al., 2020). The approach involved quantifying effects of a systemically administered NO synthase (NOS) inhibitor, N^G-monomethyl-L-arginine (L-NMMA). L-NMMA reduced the NVC response by ≈30%, without significant changes in total CBF, blood gases, arterial pressure, or whole brain metabolism. In contrast, hemodilution or phenylephrine-induced blood pressure elevation did not alter NVC.

In relation to NO, the study confirms the concept that NO plays an essential role in NVC based on non-human preclinical models. It also confirms work in humans which evaluated the role of NO in NVC in the retina (an extension of the central nervous system)(Dorner et al., 2003). From early mechanistic studies, a role for NO has been repeatedly implicated in NVC and regulation of CBF. This concept has now translated from preclinical models to human brain and retina.

Strengths of the work by Hoiland et al. include the study of awake humans using a natural visual stimulus to activate NVC. The authors include a careful and systematic quantification of various determinants of CBF. Limitations include the use of a single approach to implicate NO. Quantitative estimates of the role of NO in vascular biology are difficult. L-NMMA is used in humans but is less potent than other NOS inhibitors. Commonly used doses of L-NMMA in humans do not fully inhibit NOS (Lauer et al., 2001). Thus, although L-NMMA affected brain and retinal NVC (Dorner et al., 2003; Hoiland et al., 2020), the contribution made by NO may well be underestimated. Additional mediators very likely contribute to NVC, particularly potassium ion (Iadecola, 2017).

Future discoveries in this field of study may benefit from several lines of investigation. First, the current study does not provide insight into which isoform(s) of NOS were involved (neuronal and/or endothelial). Second, only males were studied (Dorner et al., 2003; Hoiland et al., 2020), despite the fact that conditions such as Alzheimer’s disease are more likely to be present in women. Third, studies of NVC in humans with known genetic variants that reduce or enhance NO signaling would provide an independent experimental strategy. Fourth, advances in genome editing and technologies to manipulate pluripotent stem cells (PSC) offer the potential of human PSC-derived models for mechanistic studies, testing of genetic variation, and high through-put drug discovery, focusing on individual cells in brain organoids and the neurovascular unit. Fifth, if such signally is lost at the level of neurons or within the vascular tree, what is the impact for brain health? Impaired NVC has been described in aging as well as Alzheimer’s disease, atrial fibrillation, autism spectrum disorder, diabetes, hypertension, in the presence of mutated tau, among other conditions. There are many examples where reduced NVC is associated with cognitive or memory deficits. The relative importance of reductions in resting CBF (chronic hypoperfusion) versus changes in NVC per se on brain function are poorly defined, a fertile area for future insight. Lastly, studies are needed that provide direct insight into the impact of the vascular component of conditions that result in loss of brain health, rather than work based on associations.