Advancing our k'NO'wledge for neurovascular coupling of brain blood flow in humans

Cerebral neurovascular coupling (NVC) describes the temporal interaction between pairing regional cerebral blood flow to increased neural metabolic demand and is primarily governed via signalling within the neurovascular unit. This unit is comprised of the neuron, astrocyte glial cell and vascular smooth muscle. A thorough understanding of the contributing vascular components and mechanisms that govern the NVC response is important when considering impairments in cerebrovascular control that often accompany the development of neurological disease (Iadecola, 2017). The NVC response unfolds in two discreet components, first a peak hemodynamic response mediated through neural feed-forward signalling within the neurovascular unit, and second a plateau phase of sustained increases in blood flow regulated through feed-back responses to metabolic by-product accumulation (Iadecola, 2017). Much of the understanding for mechanistic contributions to NVC is limited to reduced animal preparations. These studies illustrate the role of neuronal feed-forward signalling leading to production of nitric oxide (NO) as a primary contributor to NVC responses (Hosford & Gourine, 2019). In humans, a role for NO mediated control of the peripheral vasculature is established. However, contributions of NO signalling as a mechanism for cerebrovascular regulation, and specifically NVC control in humans has been largely unexplored. In a recent issue of The Journal of Physiology, Hoiland et al. (2020) outlined important advancements for the mechanistic understanding of NVC in humans utilizing a randomized, blinded and placebo controlled experimental design. In a cohort of healthy males, two hypotheses were tested to determine whether NVC was affected by (1) NO synthase inhibition by NG-monomethyl-L-arginine (L-NMMA) to block neuronal NO production, and by (2) isovolumic hemodilution, where ∼20% blood volume was removed and replaced with human serum albumin to attenuate the erythrocyte-dependent component of NO production. A subset of participants received a phenylephrine infusion to interrogate NVC during elevations in blood pressure independent of hypertension induced from NO synthase inhibition. The in-vivo human model for NVC measured responses to five repeated cycles of eyes-closed to eyes-open transitions while neural activation was induced via a flashing checkerboard visual stimulus. This standardized neural activation task elicited a response in the posterior cerebral artery (PCA) which was measured by transcranial Doppler ultrasound. NVC was quantified prior to, and following L-NMMA infusions or hemodilution by the absolute and relative PCA blood velocity and vascular conductance response to the visual stimulus relative to the eyes-closed phase. Additionally, global cerebral blood flow was assessed with Duplex ultrasound and cerebral metabolism was quantified by direct arterial and jugular venous blood sampling. Hoiland et al. (2020) demonstrated a ∼30% reduction in the absolute and relative peak PCA vascular conductance response following NO synthase inhibition while NVC was unchanged following a saline-control. Moreover, isovolumic hemodilution did not alter peak or average NVC responses despite noting an increase to global cerebral blood flow and conductance at rest. Mean arterial pressure was unaltered by NO synthase inhibition, and NVC was unaltered during phenylephrine induced increases in mean arterial pressure. These findings suggest NO synthase activity has a significant role in eliciting the feed-forward neurally-mediated peak NVC responses but other regulatory mechanisms (also independent of isovolumic hemodilution) may contribute to the plateau phase in healthy males. Taken together, the novel findings from Hoiland et al. (2020) provide the first evidence in humans for the role of NO signalling in NVC and outline the potential for new therapeutic targets in the management of cerebrovascular dysfunction. Notably, the finding that NVC was unaltered during phenylephrine induced increases to mean arterial pressure, and elevated cerebrovascular conductance following isovolumic hemodilution may suggest that broader mechanical features of the cerebrovascular circulation may contribute to NVC. Recently, vascular compliance has been identified as an important component of cerebrovascular regulation and may represent an independent predictor of disease. Cerebrovascular compliance discreetly governs a component of cerebral blood flow regulation during a sit-to-stand maneuver in humans. Moir and colleagues (2020) showed a transient increase in vascular compliance precedes the arterial resistance response contributing to the maintenance of cerebral blood flow during a perturbation to blood pressure. Both cerebral autoregulation, and NVC describe fundamental processes pertinent to the reflex response and maintenance of cerebral blood flow during physiological perturbations. Therefore, we wonder whether vascular compliance plays a role in cerebrovascular control during NVC processes. To our knowledge, no work to date has examined a role for vascular compliance in NVC in animal or human models. Fundamentally, vascular compliance relates to the structural elements of the vascular wall including smooth muscle cells, elastin, and collagen. Alterations in vascular compliance can occur through active processes related to vascular smooth muscle cells. Reductions in wall tension that accompany smooth muscle cell relaxation increases vascular compliance (Bank et al., 1995). In contrast, vasodilation reduces vascular compliance as collagen fibers become stretched contributing to stiffer vessels (Bank et al., 1995). Therefore, inputs which alter smooth muscle cell contractile state likely influence vascular compliance. Neural, myogenic, and metabolic inputs regulate vascular compliance in the forearm vascular bed (Bank et al., 1995). It is reasonable to expect that neural, myogenic, and metabolic mechanisms would also regulate cerebrovascular compliance given that these inputs contribute to vasomotor adjustments in the brain. However, while these mechanisms regulate both peripheral and cerebral vessels, we acknowledge that the magnitude of their effect may vary by vascular bed. As metabolic components largely contribute to NVC responses, vascular compliance may be affected in addition to vascular conductance. More precisely, we wonder if NO-mediated smooth muscle relaxation in the NVC model would augment vascular compliance. Observation of increased vascular compliance following sodium nitroglycerin administration in humans (Bank et al., 1995) supports this notion. However, vasodilation of the PCA vascular bed may attenuate vascular compliance. The conflicting outcomes may relate to the temporal nature of the response. With dynamic cerebral autoregulatory responses in humans, initiated by reductions in blood pressure, rapid increases in vascular compliance preceded cerebral vasodilation and upon initiation of vasodilation, vascular compliance returned to baseline (Moir et al., 2020). One interpretation for the diverging vascular compliance and resistance responses was initial myogenic-mediated relaxation of the smooth muscle cells prior to the onset of observable vasodilation (Moir et al., 2020). Whether metabolic processes such as NVC would demonstrate similar temporal profiles in vascular compliance and conductance remains unknown. Nonetheless, NVC processes may involve rapid increases in vascular compliance related to feed-forward neuronal signalling and initial NO-mediated relaxation of smooth muscle cells, followed by the return of vascular compliance to baseline or reductions below baseline once PCA dilation begins. Therefore, vascular compliance may contribute to peak PCA velocity responses mediated by feed-forward NO-dependent mechanisms. However, following a rapid peak compliance response, reductions in vascular compliance may occur with sustained PCA vasodilation. Thus, vascular compliance may not contribute, at least to a great extent, to feed-back NVC mechanisms contributing to the plateau phase of the response. In addition to active changes in vascular smooth muscle cells, vascular compliance may be modified passively by transmural pressure. Elastin and collagen express unique functional characteristics whereby their contribution to elastic wall tension depends on distending pressure. In healthy adults, blood pressure remains relatively unchanged during NVC responses. Further, the findings from Hoiland and colleagues (2020) demonstrate that increased blood pressure, induced by phenylephrine, did not influence NVC responses. Nonetheless, alterations in blood pressure during NVC may influence vascular compliance. Unique to the cerebrovascular bed, intracranial pressure influences the ability of the cerebral vessels to express their elasticity whereby reductions in intracranial pressure enable increased vascular compliance (Moir et al., 2020). The effect of NVC on intracranial pressure remains unclear in humans. Overall, complex integrative mechanisms contribute to cerebrovascular compliance. While alterations in smooth muscle cell contractile state are expected during NVC processes, how these metabolically-mediated changes might influence vascular compliance remain elusive. Further, transmural pressure changes that may occur concomitantly with changes in smooth muscle cell contractile state, likely also impact vascular compliance. Therefore, potential contributions of vascular compliance to NVC responses represent an important avenue of future research. The findings from Hoiland et al., (2020) substantially advance our understanding for the control of NVC in humans. Importantly, reductions to NVC are observed with aging, and in clinical populations where often increases in vascular stiffness, pulse-wave velocity, and hypertension prevail. Given that Hoiland et al., (2020) report a reduced peak but not average NVC following NO synthase inhibition, additional pathways independent of NO signalling may be responsible for altered NVC across cohorts and contributing factors to the integrative control of NVC in humans is not fully resolved. Notably, our understanding for the role of vascular compliance in cerebrovascular regulation remains in its infancy. While alterations in vascular resistance or conductance constitute an integral component of cerebral blood flow regulation, vascular compliance represents an additional mechanism of control, at least during cerebral autoregulatory responses to transient blood pressure reductions (Moir et al., 2020). In summary, future studies should aim to evaluate whether vascular compliance represents an additional complementary response during NVC processes in humans in health and disease. None. M.E.M. & T.D.V. contributed equally to all aspects of this work. M.E.M. is supported by an Ontario Graduate Scholarship & T.D.V. is supported by a NSERC Doctoral Scholarship. We thank Prof. J. Kevin Shoemaker for providing critical feedback to this manuscript.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.