Cerebrovascular Regulation Research Articles

Vegetative and cerebrovascular regulation in vestibular dysfunctions of ischemic origin

Vestibular dysfunction (VD) is a common syndrome of ischemic brain damage that occurs with pronounced vegetative accompaniment, cerebrovascular regulation disorder. 62 patients with VD on the background of chronic brain ischemia in the compensated (I group n = 24) and subcompensated (II group n = 38) stages were examined (40.3 % men; 59.7 % women), age from 18 to 55 years, average age was 38.6 ± 1.6 years. In case of ischemic damage to the brain due to degenerative-dystrophic changes in the cerebral cortex, certain mechanisms of the development of VD with dizziness have been registered. Their presence in the clinical picture of vascular dyshemia correlates with the degree of damage, is ac- companied by pain, as well as associated complaints and symptoms. Vestibulo-atactic disorders, recorded using the integrative state of statolocomotor, were elevated compared to healthy subjects, and further increased depending on the degree of brain damage, especially against the background of prevailing vagotonia in most patients. Autonomic dysfunctions are an important aspect of the development of VD. The obtained data indicate that VD develops against the background of pathological autonomic characteristics with predominant parasympathetic orientation of vegetative tone, especially in the case of insufficiency of vegetative reactivity and pathological vegetative maintenance of activity. Such changes significantly (p < 0.05) increased in the presence of subcompensation of the chronic brain ischemia. Psychoemotional and cognitive disorders are comorbid according to the changed autonomic characteristics in VD on the background of chronic brain ischemia with initial patterns depending on the degree of brain damage. A characteristic hemodynamic feature in the groups with compensated and subcompensated chronic brain ischemia is the presence of reduced perfusion in main artery and vertebral artery. Significant changes in cerebral vascular reactivity along the myogenic circuit with a decrease in KrO2 and KrFNT indicators are a characteristic feature of the subcompensated stage of chronic brain ischemia. Hyperreactivity on rotational functional loads in both clinical groups has a high correlation with the presence of staircase and, to a lesser extent, isolated instability.

DAILY EXERCISE DOES NOT ALTER CEREBRAL BLOOD FLOW REGULATION DURING TILT IN OLDER ADULTS AFTER TWO WEEKS OF BEDREST

Abstract Bedrest is associated with cardiovascular and cerebrovascular changes that are linked to a greater prevalence of orthostatic intolerance; however, much of what we know from bedrest trials comes from young adults. How older adults respond to extended periods of activity restriction is not well understood. The current work tested the hypothesis that impaired control of cerebral blood flow in older adults following bedrest could be attenuated by regular exercise. Twenty-two older adults (55-65 years, 11 women) participated in a randomized controlled trial involving 14 days of continuous 6-degree head-down bedrest. The cohort was randomized to an exercise intervention (EX), involving daily aerobic, high-intensity interval, and resistance training, or a control group (CON), involving passive manual therapy. Cerebral blood flow velocity, cardiac output, and arterial blood pressure were measured continuously during a passive 80-degree head-up tilt protocol for up to 15 minutes. Responses in the cerebral and peripheral vascular beds were quantified by vascular resistance (cerebral: resistance area product (RAP); peripheral: total peripheral resistance (TPR)). Following bedrest, both supine RAP and TPR were elevated (p< 0.01), with no effect of exercise training. In addition, the number of participants who could not complete 15 minutes of tilt increased from 3 to 15 (8 EX, 7 CON). In these non-finishers, RAP dropped ~20% and TPR dropped ~15% during the final 2 minutes of tilt, with no difference between groups. These data suggest that multimodal exercise training is insufficient to prevent changes in cardiovascular and cerebrovascular regulation in older adults observed during 14-day bedrest.

Respiratory training in older women: Unravelling central and peripheral hemodynamic slow oscillatory patterns

We hypothesized that inspiratory muscle training (IMT) increases the respiratory-induced low-frequency oscillations of mean blood pressure (MBP) and middle cerebral artery blood velocity (MCAv), upregulating cerebrovascular function in older women. Firstly, participants were recorded with free-breathing (FB) and then breathed at a slow-paced frequency (0.1 Hz; DB test) supported by sonorous metronome feedback. Blood pressure was recorded using finger photoplethysmography method, ECG, and respiration using a thoracic belt. To obtain the MCAv a transcranial ultrasound Doppler device was used. Spectral analysis of MBP, R-R intervals, and mean MCAv time series was obtained by an autoregressive model. The transfer function analysis (TFA) was employed to calculate the coherence, gain, and phase. After that, older women were enrolled in a randomized controlled protocol, the IMT-group (n = 8; 64 ± 3 years-old) performed IMT at 50 % of maximal inspiratory pressure (MIP), and Sham-group, a placebo training at 5 % MIP (Sham-group; n = 6; 66 ± 3 years-old). Participants breathed against an inspiratory resistance twice a day for 4-weeks. DB test is repeated post IMT and Sham interventions. IMT-group, compared to Sham-group, augmented tidal volume responses to DB (Sham-group 1.03 ± 0.41 vs. IMT-group 1.61 ± 0.56 L; p = 0.04), increased respiratory-induced MBP (Sham-group 26.37 ± 4.46 vs. IMT-group 48.21 ± 3.15 mmHg2; p = 0.04) and MCAv (Sham-group 14.16 ± 31.26 vs. IMT-group 79.90 ± 21.76 cm2s−2; p = 0.03) slow oscillations, and reduced TFA gain (Sham-group 2.46 ± 1.32 vs. IMT-group 1.78 ± 1.30 cm·s−1.mmHg−1; p = 0.01). Our findings suggest that IMT increases the respiratory-induced oscillations in MBP and MCAv signals and reduces TFA gain. It seems compatible with an improved dynamic cerebrovascular regulation following IMT in older women.

Spectral decomposition of cerebrovascular and cardiovascular interactions in patients prone to postural syncope and healthy controls

We present a framework for the linear parametric analysis of pairwise interactions in bivariate time series in the time and frequency domains, which allows the evaluation of total, causal and instantaneous interactions and connects time- and frequency-domain measures. The framework is applied to physiological time series to investigate the cerebrovascular regulation from the variability of mean cerebral blood flow velocity (CBFV) and mean arterial pressure (MAP), and the cardiovascular regulation from the variability of heart period (HP) and systolic arterial pressure (SAP). We analyze time series acquired at rest and during the early and late phase of head-up tilt in subjects developing orthostatic syncope in response to prolonged postural stress, and in healthy controls. The spectral measures of total, causal and instantaneous coupling between HP and SAP, and between MAP and CBFV, are averaged in the low-frequency band of the spectrum to focus on specific rhythms, and over all frequencies to get time-domain measures. The analysis of cardiovascular interactions indicates that postural stress induces baroreflex involvement, and its prolongation induces baroreflex dysregulation in syncope subjects. The analysis of cerebrovascular interactions indicates that the postural stress enhances the total coupling between MAP and CBFV, and challenges cerebral autoregulation in syncope subjects, while the strong sympathetic activation elicited by prolonged postural stress in healthy controls may determine an increased coupling from CBFV to MAP during late tilt. These results document that the combination of time-domain and spectral measures allows us to obtain an integrated view of cardiovascular and cerebrovascular regulation in healthy and diseased subjects.

Cerebrovascular regulation in patients with vasovagal syncope and autonomic failure due to familial amyloidotic polyneuropathy.

While there is strong evidence for autonomic involvement in cerebrovascular function acutely, long-term role of autonomic nervous system in cerebrovascular function has been controversial. We assessed autoregulation in 10 healthy individuals, nine patients with vasovagal syncope (VVS), and nine with Familial Amyloidotic Polyneuropathy (FAP), in response to head-up tilt test (HUTT). Arterial blood pressure heart rate, cardiac output, and bilateral cerebral blood flow velocity (CBFV) at the M1 segment of middle cerebral artery (transcranial Doppler ultrasound) were recorded during supine rest and 70° HUTT. Autoregulation was quantified using a validated nonlinear and nonparametric approach based on projection pursuit regression. Plasma adrenaline and noradrenaline were also measured at rest and during HUTT. During supine rest and HUTT, plasma noradrenaline content was lower in FAP patients. During HUTT, VVS patients had a hyperadrenergic status; CBFV decreased in all groups, which was greater in FAP patients (p<0.01). Healthy controls responded to HUTT with a reduction in CBFV responses to increases (p=0.01) and decreases (p<0.01) in arterial pressure without any change in the range or effectiveness of autoregulation. VVS patients responded to HUTT with a reduction in falling (p=0.02), but not rising slope (p=0.40). Autoregulatory range (p<0.01) and effectiveness increased (p=0.09), consistent with the rapid increase in levels of catecholamines. In FAP patients, the level of increase in range of autoregulation was significantly related to the magnitude of increase in plasma noradrenaline in response to HUTT (R2=0.26, p=0.05). Autonomic dysfunction affects the cerebral autoregulatory response orthostatic to challenge.

Cerebrovascular Regulation In Response To High-intensity Interval Exercise

Cerebrovascular Regulation In Response To High-intensity Interval Exercise

Brain-muscle interplay during endurance self-paced exercise in normobaric and hypobaric hypoxia.

Purpose: Hypoxia is one major environmental factor, supposed to mediate central motor command as well as afferent feedbacks at rest and during exercise. By using a comparison of normobaric (NH) and hypobaric (HH) hypoxia with the same ambient pressure in oxygen, we examined the potential differences on the cerebrovascular and muscular regulation interplay during a self-paced aerobic exercise. Methods: Sixteen healthy subjects performed three cycling time-trials (250 kJ) in three conditions: HH, NH and normobaric normoxia (NN) after 24 h of exposure. Cerebral and muscular oxygenation were assessed by near-infrared spectroscopy, cerebral blood flow by Doppler ultrasound system. Gas exchanges, peripheral oxygen saturation, power output and associated pacing strategies were also continuously assessed. Results: The cerebral oxygen delivery was lower in hypoxia than in NN but decreased similarly in both hypoxic conditions. Overall performance and pacing were significantly more down-regulated in HH versus NH, in conjunction with more impaired systemic (e.g. saturation and cerebral blood flow) and prefrontal cortex oxygenation during exercise. Conclusions: The difference in pacing was likely the consequence of a complex interplay between systemic alterations and cerebral oxygenation observed in HH compared to NH, aiming to maintain an equivalent cerebral oxygen delivery despite higher adaptive cost (lower absolute power output for the same relative exercise intensity) in HH compared to NH.

Atogepant for migraine.

Atogepant is a selective oral, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that has been approved for preventive treatment of migraine. CGRP is a neuropeptide involved in vasodilation and cerebrovascular regulation. CGRP is the most potent vasoactive constituent of the cerebrovascular trigeminal neuronal system and has a key role in migraine. Medications targeting CGRP are being used as migraine preventive and abortive treatments.

In vivo Single Cell Optical Ablation of Brain Pericytes.

Pericytes have myriad functions in cerebrovascular regulation but remain understudied in the living brain. To dissect pericyte functions in vivo, prior studies have used genetic approaches to induce global pericyte loss in the rodent brain. However, this leads to complex outcomes, making it challenging to disentangle the physiological roles of pericytes from the pathophysiological effects of their depletion. Here, we describe a protocol to optically ablate individual pericytes of the mouse cerebral cortex in vivo for fine-scale studies of pericyte function. The strategy relies on two-photon microscopy and cranial window-implanted transgenic mice with mural cell-specific expression of fluorescent proteins. Single pericyte somata are precisely targeted with pulsed infrared laser light to induce selective pericyte death, but without overt blood-brain barrier leakage. Following pericyte ablation, the changes to the local capillary network and remaining pericytes can be examined longitudinally. The approach has been used to study pericyte roles in capillary flow regulation, and the structural remodeling of pericytes involved in restoration of endothelial coverage after pericyte loss.

URB597 and Andrographolide Improve Brain Microvascular Endothelial Cell Permeability and Apoptosis by Reducing Oxidative Stress and Inflammation Associated with Activation of Nrf2 Signaling in Oxygen-Glucose Deprivation.

Ischemic stroke, a cerebrovascular disease worldwide, triggers a cascade of pathophysiological events, including blood-brain barrier (BBB) breakdown. Brain microvascular endothelial cells (BMECs) play a vital role in maintaining BBB function. The injury of BMECs may worsen neurovascular dysfunction and patients' prognosis. Therefore, uncover the principal molecular mechanisms involved in BBB disruption in stroke becomes pressing. The endocannabinoid system (ECS) has been implicated in increasingly physiological functions, both in neurometabolism and cerebrovascular regulation. Modulating its activities by the fatty acid amide hydrolase (FAAH) shows anti-inflammatory characteristics. Andrographolide (AG), one Chinese herbal ingredient, has also attracted attention for its role in immunomodulatory and as a therapeutic target in BBB disorders. Recently, the FAAH inhibitor URB597 and AG have important regulatory effects on neuronal and vascular cells in ischemia. However, the effects of URB597 and AG on BMEC permeability and apoptosis in oxygen-glucose deprivation (OGD) and the underlying mechanisms remain unclear. To address these issues, cultured BMECs (bEnd.3 cells) were exposed to OGD. The cell viability, permeability, tube formation, and apoptosis were assessed following treatment with URB597, AG, and cotreatment. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), proinflammatory factors, tight junction (TJ) proteins, and oxidative stress-mediated Nrf2 signaling were also investigated. Results revealed that OGD broke the endothelial barrier, cell viability, MMP, and tube formation, which was reversed by URB597 and AG. OGD-induced enhancement of ROS, MDA, and apoptosis was reduced after drug interventions. URB597 and AG exhibited antioxidant/anti-inflammatory and mitochondrial protective effects by activating Nrf2 signaling. These findings indicated that URB597 and AG protect BMECs against OGD-induced endothelial permeability impairment and apoptosis by reducing mitochondrial oxidative stress and inflammation associated with activation of Nrf2 signaling. URB597 and AG showing the vascular protection may have therapeutic potential for the BBB damage in ischemic cerebrovascular diseases.

Cerebral autoregulation across the menstrual cycle in eumenorrheic women.

There is emerging evidence that ovarian hormones play a significant role in the lower stroke incidence observed in pre‐menopausal women compared with men. However, the role of ovarian hormones in cerebrovascular regulation remains to be elucidated. We examined the blood pressure‐cerebral blood flow relationship (cerebral autoregulation) across the menstrual cycle in eumenorrheic women (n = 12; mean ± SD: age, 31 ± 7 years). Participants completed sit‐to‐stand and Valsalva maneuvers (VM, mouth pressure of 40 mmHg for 15 s) during the early follicular (EF), late follicular (LF), and mid‐luteal (ML) menstrual cycle phases, confirmed by serum measurement of progesterone and 17β‐estradiol. Middle cerebral artery blood velocity (MCAv), arterial blood pressure and partial pressure of end‐tidal carbon dioxide were measured. Cerebral autoregulation was assessed by transfer function analysis during spontaneous blood pressure oscillations, rate of regulation (RoR) during sit‐to‐stand maneuvers, and Tieck’s autoregulatory index during VM phases II and IV (AI‐II and AI‐IV, respectively). Resting mean MCAv (MCAvmean), blood pressure, and cerebral autoregulation were unchanged across the menstrual cycle (all p > 0.12). RoR tended to be different (EF, 0.25 ± 0.06; LF; 0.19 ± 0.04; ML, 0.18 ± 0.12 sec−1; p = 0.07) and demonstrated a negative relationship with 17β‐estradiol (R2 = 0.26, p = 0.02). No changes in AI‐II (EF, 1.95 ± 1.20; LF, 1.67 ± 0.77 and ML, 1.20 ± 0.55) or AI‐IV (EF, 1.35 ± 0.21; LF, 1.27 ± 0.26 and ML, 1.20 ± 0.2) were observed (p = 0.25 and 0.37, respectively). Although, a significant interaction effect (p = 0.02) was observed for the VM MCAvmean response. These data indicate that the menstrual cycle has limited impact on cerebrovascular autoregulation, but individual differences should be considered.

Exercise and Hypercapnia Differentially Modify Ratios of Extracranial and Intracranial Pulsatility

INTRODUCTIONDamping of pulsatile flow between extracranial and intracranial cerebral arteries is an essential allostatic mechanism protecting cerebral microvessels from recalcitrant hemodynamics. The ratio of pulsatility between proximal and distal cerebral arteries may provide a measure of cerebrovascular hemodynamic damping. This might prove useful as an evaluation of cerebrovascular regulation in response to pulsatile perturbations.PURPOSETo characterize cerebral pulsatile damping between extracranial and intracranial environments in response to perturbations eliciting matched shear stress, such as exercise and hypercapnia.METHODSParticipants (n=10) completed two 30‐min experimental conditions aimed at matching cerebral artery shear stress, each separated by 48 hrs: (1) mild hypercapnia (CO2; FICO2:0.045) and (2) submaximal cycling (EX; 60%HRreserve). Cerebral pulsatility index (PI: (systolic velocity‐diastolic velocity)/mean velocity)) was assessed at baseline, during, and following each condition in the internal carotid artery (ICA) and middle cerebral artery (MCA) using Doppler ultrasound. Heart rate (HR) and blood pressure (BP) were assessed continuously using ECG and photoplethysmography, respectively. Cerebral pulsatile damping was calculated: (ICA PI / MCA PI) to investigate ratios of cerebral pulsatile hemodynamics between extracranial and intracranial arteries.RESULTSCerebral pulsatile damping was greater during CO2 (1.66 ± 0.31) than EX (1.22 ± 0.35) (time*condition effect, p=0.002). The change in cerebral pulsatile damping was related to the change in heart rate (r = ‐0.70, p = 0.04), but not BP between baseline and the experimental conditions.CONCLUSIONSAs evidenced by the response in cerebral pulsatile damping, exercise and hypercapnia result in different ratios of extracranial to intracranial pulsatility despite inducing similar vasodilation when shear stress was matched. This might in part be explained by differences in HR between conditions. Further research is important to elucidate the mechanisms behind the deviance in hemodynamic responses.

Altered cerebrovascular regulation in low birthweight swine

Full-term low birthweight (LBW) offspring exhibit peripheral vascular dysfunction in the postnatal period; however, whether such impairments extend to the cerebrovasculature remains to be elucidated. We used a swine model to test the hypothesis that LBW offspring would exhibit cerebrovascular dysfunction at later stages of life. Offspring from 14 sows were identified as normal birthweight (NBW) or LBW and were assessed at 28 (similar to end of infancy) and 56 (similar to childhood) days of age. LBW swine had lower absolute brain mass, but demonstrated evidence of brain sparing (increased brain mass scaled to body mass) at 56 days of age. The cerebral pulsatility index, based on transcranial Doppler, was increased in LBW swine. Moreover, arterial myography of isolated cerebral arteries revealed impaired vasoreactivity to bradykinin and reduced contribution of nitric oxide (NO) to vasorelaxation in the LBW swine. Immunoblotting demonstrated a lower ratio of phosphorylated-to-total endothelial NO synthase in LBW offspring. This impairment in NO signaling was greater at 28 vs. 56 days of age. Vasomotor responses to sodium nitroprusside (NO-donor) were unaltered, while Leu31, Pro34 neuropeptide Y-induced vasoconstriction was enhanced in LBW swine. Increases in total Y1 receptor protein content in the LBW group were not significant. In summary, LBW offspring displayed signs of cerebrovascular dysfunction at 28 and 56 days of age, evidenced by altered cerebral hemodynamics (reflective of increased impedance) coupled with endothelial dysfunction and altered vasomotor control. Overall, the data reveal that normal variance in birthweight of full-term offspring can influence cerebrovascular function later in life.

Cerebrovascular Regulation in Response to High-intensity Interval Exercise

Cerebrovascular Regulation in Response to High-intensity Interval Exercise

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

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

Acid-base balance and cerebrovascular regulation.

The regulation and defence of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid-base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid-base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension (PCO2 ), bicarbonate (HCO3- ) and pH. These factors interact to influence (1) the time course of acid-base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial blood, extracellular fluid and intracellular brain tissue). We propose that alterations in arterial [HCO3- ] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid-base regulation; and (2) the regulation of CBF by direct changes in arterial vs. extravascular/interstitial PCO2 and pH - the latter recognized as the proximal compartment which alters vascular smooth muscle cell regulation of CBF. Taken together, these results substantiate two key ideas: first, that the regulation of CBF is affected by the severity of metabolic/respiratory disturbances, including the extent of partial/full acid-base compensation; and second, that the regulation of CBF is independent of arterial pH and that diffusion of CO2 across the blood-brain barrier is integral to altering perivascular extracellular pH. Overall, by realizing the integrative relationships between CBF, PCO2 , HCO3- and pH, experimental studies may provide insights to improve CBF regulation in clinical practice with treatment of systemic acid-base disorders.

Neurovascular Coupling Is Impaired in Hypertensive and Diabetic Subjects Without Symptomatic Cerebrovascular Disease.

The mechanistic link between hypertension, diabetes and cerebral small vessel disease (CSVD) is still poorly understood. We hypothesized that hypertension and diabetes could impair cerebrovascular regulation prior to irreversibly established cerebrovascular disease. In this study, 52 hypertensive patients [54% males; age 64 ± 11 years; 58% with comorbid diabetes mellitus (DM)] without symptomatic cerebrovascular disease underwent transcranial Doppler (TCD) monitoring in the middle (MCA) and posterior (PCA) cerebral arteries, to assess vasoreactivity to carbon dioxide (VRCO2) and neurovascular coupling (NVC). 1.5T magnetic resonance imaging was also performed and white matter hyperintensity volume was automatically segmented from FLAIR sequences. TCD data from 17 healthy controls were obtained for comparison (47% males; age 60 ± 16 years). Hypertensive patients showed significant impairment of NVC in the PCA, with reduced increment in cerebral blood flow velocity during visual stimulation (22.4 ± 9.2 vs. 31.6 ± 5.7, p < 0.001), as well as disturbed NVC time-varying properties, with slower response (lower rate time: 0.00 ± 0.02 vs. 0.03 ± 6.81, p = 0.001), and reduced system oscillation (reduced natural frequency: 0.18 ± 0.08 vs. 0.22 ± 0.06, p < 0.001), when compared to controls. VRCO2 remained relatively preserved in MCA and PCA. These results were worse in hypertensive diabetic patients, with lower natural frequency (p = 0.043) than non-diabetic patients. White matter disease burden did not predict worse NVC. These findings suggest that hypertensive diabetic patients may have a precocious impairment of NVC, already occurring without symptomatic CSVD. Future research is warranted to evaluate whether NVC assessment could be useful as an early, non-invasive, surrogate marker for CSVD.

Differences in cerebrovascular regulation and ventilatory responses during ramp incremental cycling in children, adolescents, and adults.

Regulation of cerebral blood flow during exercise in youth is poorly understood. This study investigated the cerebrovascular and ventilatory responses to a ramp incremental cycle test to exhaustion in 14 children (means ± SD age: 9.4 ± 0.9 yr), 14 adolescents (12.4 ± 0.4 yr), and 19 adults (23.4 ± 2.5 yr). Middle cerebral artery blood velocity (MCAv), partial pressure of end-tidal CO2 ([Formula: see text]), and ventilatory parameters were analyzed at baseline, gas exchange threshold (GET), respiratory compensation point (RCP), and exhaustion. The increase in minute ventilation relative to CO2 production during exercise was also calculated (V̇e/V̇co2 slope). Relative change from baseline (Δ%) in MCAv was lower in children, compared with adolescents and adults at GET [15 ± 10% vs. 26 ± 14%, and 24 ± 10%, respectively, P ≤ 0.03, effect size (d) = 0.9] and RCP (13 ± 11% vs. 24 ± 16% and 27 ± 15%, respectively, P ≤ 0.05, d ≥ 0.8). Δ%MCAv was similar in adults and adolescents at all intensities and similar in all groups at exhaustion. The magnitude of the V̇E/V̇co2 slope was negatively associated with Δ%MCAv at GET and RCP across all participants (P ≤ 0.01, r = -0.37 to -0.48). Δ%[Formula: see text] was smaller in children and adolescents compared with adults at GET and RCP (P ≤ 0.05, d ≥ 0.6). In children, Δ%[Formula: see text] and Δ%MCAv were not associated from baseline-GET (r¯=0.14) and were moderately associated from RCP-exhaustion (r¯=0.49). These relationships strengthened with increasing age and were stronger in adolescents (baseline-GET: r¯=0.47, RCP-exhaustion: r¯=0.62) and adults (baseline-GET: r¯=0.66, RCP-exhaustion: r¯=0.78). These findings provide the first evidence on the development of the regulatory role of [Formula: see text] on MCAv during exercise in children, adolescents, and adults.NEW & NOTEWORTHY This is the first study to observe similar increases in cerebral blood flow during incremental exercise in adolescents and adults. Increases in cerebral blood flow during exercise were smaller in children compared with adolescents and adults and were associated with a greater V̇E/V̇co2 slope. This study also provides the first evidence on the progressive development of the regulatory role of end-tidal CO2 on cerebral blood flow during exercise during the transition from childhood to adulthood.

Cerebrovascular insufficiency and amyloidogenic signaling in Ossabaw swine with cardiometabolic heart failure.

Individuals with heart failure (HF) frequently present with comorbidities, including obesity, insulin resistance, hypertension, and dyslipidemia. Many patients with HF experience cardiogenic dementia, yet the pathophysiology of this disease remains poorly understood. Using a swine model of cardiometabolic HF (Western diet+aortic banding; WD-AB), we tested the hypothesis that WD-AB would promote a multidementia phenotype involving cerebrovascular dysfunction alongside evidence of Alzheimer’s disease (AD) pathology. The results provide evidence of cerebrovascular insufficiency coupled with neuroinflammation and amyloidosis in swine with experimental cardiometabolic HF. Although cardiac ejection fraction was normal, indices of arterial compliance and cerebral blood flow were reduced, and cerebrovascular regulation was impaired in the WD-AB group. Cerebrovascular dysfunction occurred concomitantly with increased MAPK signaling and amyloidogenic processing (i.e., increased APP, BACE1, CTF, and Aβ40 in the prefrontal cortex and hippocampus) in the WD-AB group. Transcriptomic profiles of the stellate ganglia revealed the WD-AB group displayed an enrichment of gene networks associated with MAPK/ERK signaling, AD, frontotemporal dementia, and a number of behavioral phenotypes implicated in cognitive impairment. These provide potentially novel evidence from a swine model that cerebrovascular and neuronal pathologies likely both contribute to the dementia profile in a setting of cardiometabolic HF.

Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans.

AimsNeuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity.Methods and resultsWe investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n = 19). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an ∼4% decrease in resting global CBF [−2.3 (−0.3, −4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T = 7.0; x = 36; y = −32; z = −12; P < 0.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T = 5.02; x = −14; y = −56; z = 74; P = 0.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7 mmHg (+1.8, +15.6), mean (95% CI), P = 0.009].ConclusionsThese data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease.