Cerebral Vascular Function Research Articles

NIH Toolbox Cognitive Battery in non-Hispanic Black individuals: role of cerebral vascular function, pulse wave velocity, and psychosocial stress exposure

Non-Hispanic Black (BL) individuals are ~ 2 times more likely to develop cognitive impairment, Alzheimer’s disease, and related dementias (ADRD) relative to other populations. ADRD prevalence is expected to double by 2060, with a greater increase in BL and Hispanic populations. Reduced cerebral vascular function and large elastic artery health increases risk for cognitive decline and ADRD. In addition, psychosocial stress exposure, including at a young age, is a significant predictor of intellectual function and executive attention. However, the relationship between 1) cerebral & peripheral vascular function/health and indices of cognitive function, and 2) psychosocial stress exposure and indices of cognitive function in relatively young, healthy BL individuals are incompletely understood. We tested the hypothesis that cerebral vascular function and large elastic artery health are blunted in BL individuals, which will be associated with reduced cognitive performance. We also hypothesized that psychosocial stress exposure in the BL individuals is negatively associated with cognitive performance. METHODS: Eight BL (2 males; age: 20±1 yr; BMI: 22±3 kg/m2) and 8 WH (4 males; age: 20±3 yr; BMI: 23±2 kg/m2) individuals participated. Cognitive function was indexed using the NIH Toolbox Cognitive Battery which compiles a fluid score (i.e., capacity for new learning and information processing in novel situations), a crystallized score (i.e., past learning experiences), and a total cognition score. Cerebral vascular function was assessed as the % increase in cerebral vascular conductance (CVCi = middle cerebral artery blood velocity/mean arterial pressure) during hypercapnia (6% CO2). Large elastic artery health was assessed as aortic pulse wave velocity (PWV). Psychosocial stress exposure was assessed as adverse childhood experiences (ACEs). RESULTS: The national percentile and age-adjusted fluid and total scores were lower in the BL individuals ( P<0.05 for each), whereas the crystallized score was not different ( P=0.79). The % increase in CVCi during hypercapnia (BL: 32±15, WH: 54±50%, P=0.26) and PWV (BL: 5.7±0.9, WH: 5.7±0.9 m·s-1, P=0.96) was similar between groups. Within the BL individuals there was not a significant correlation between %CVCi or PWV and the fluid, crystallized, or total scores ( P>0.05 for each) while ACEs tended to be negatively associated with total ( P=0.06) but not fluid or crystallized scores ( P>0.05 for each). CONCLUSION: These preliminary data suggest that young, healthy BL individuals may have reduced indices of cognitive function, particularly in the fluid domain, which may be associated with ACEs. This does not appear to be related to cerebral vascular function or large elastic artery stiffness. Future work will continue to assess these relationships in a population with a wider age range and more diverse life experiences. NIH R15 (HL156128, RMB) & Peanut Institute (982307, RMB) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiovascular and cerebral vascular health in females with postacute sequelae of COVID-19.

Many individuals who had coronavirus disease 2019 (COVID-19) develop detrimental persistent symptoms, a condition known as postacute sequelae of COVID-19 (PASC). Despite the elevated risk of cardiovascular disease following COVID-19, limited studies have examined vascular function in PASC with equivocal results reported. Moreover, the role of PASC symptom burden on vascular health has not been examined. We tested the hypothesis that peripheral and cerebral vascular function would be blunted and central arterial stiffness would be elevated in patients with PASC compared with age-matched controls. Furthermore, we hypothesized that impairments in vascular health would be greater in those with higher PASC symptom burden. Resting blood pressure (BP; brachial and central), brachial artery flow-mediated dilation (FMD), forearm reactive hyperemia, carotid-femoral pulse wave velocity (PWV), and cerebral vasodilator function were measured in 12 females with PASC and 11 age-matched female controls without PASC. The severity of persistent symptoms in those with PASC was reported on a scale of 1-10 (higher score: greater severity). Brachial BP (e.g., systolic BP, 126 ± 19 vs.109 ± 8 mmHg; P = 0.010), central BP (P < 0.050), and PWV (7.1 ± 1.2 vs. 6.0 ± 0.8 m/s; P = 0.015) were higher in PASC group compared with controls. However, FMD, reactive hyperemia, and cerebral vasodilator function were not different between groups (P > 0.050 for all). Total symptom burden was not correlated with any measure of cardiovascular health (P > 0.050 for all). Collectively, these findings indicate that BP and central arterial stiffness are elevated in females with PASC, whereas peripheral and cerebral vascular function appear to be unaffected, effects that appear independent of symptom burden.NEW & NOTEWORTHY We demonstrate for the first time that resting blood pressure (BP) and central arterial stiffness are higher in females with PASC compared with controls. In contrast, peripheral and cerebral vascular functions appear unaffected. Moreover, there was no relationship between total PASC symptom burden and measures of BP, arterial stiffness, or vascular function. Collectively, these findings suggest that females with PASC could be at greater risk of developing hypertension, which appears independent of symptom burden.

High pulse pressure impairs cerebral artery endothelial function in young, but not old, mice

One of the hallmarks of vascular aging is increased pulse pressure. This elevated pulse pressure is associated with deleterious effects on cerebral vascular function; however, it is unknown if age modulates the susceptibility to high pulse pressure. To examine the effects of age on the cerebral artery response to pulse pressure, we studied isolated cerebral arteries collected from young (6.1 ± 0.2 mo) and old (26.7 ± 0.5 mo) male C57BL/6 mice. Isolated cerebral arteries were exposed ex vivo to static pressure, low pulse pressure (25 mmHg), and high pulse pressure (50 mmHg). In cerebral arteries from young mice, endothelium-dependent dilation was similar between the static and low pulse pressure conditions. Exposure to high pulse pressure impaired endothelium-dependent dilation in cerebral arteries from young mice, mediated by less nitric oxide bioavailability and greater oxidative stress. Cerebral arteries from old mice had impaired cerebral artery endothelium-dependent dilation at static pressure compared with young cerebral arteries. However, exposure to low or high pulse pressure did not cause any further impairments to endothelium-dependent dilation in old cerebral arteries compared with static pressure. The old cerebral arteries had less distension during exposure to high pulse pressure and greater stiffness compared with young cerebral arteries. These results indicate that acute exposure to high pulse pressure impairs endothelium-dependent dilation in young, but not old, cerebral arteries. The greater stiffness of cerebral arteries from old mice potentially protects against the negative consequences of high pulse pressure.

Comparison of peripheral and cerebral vascular function between premenopausal, early and late postmenopausal females.

What is the central question of this study? We sought to investigate whether peripheral and cerebrovascular function are impaired in early and late postmenopausal females compared with premenopausal females, while also accounting for nitric oxide and estradiol levels. What is the main finding and its importance? We observed no differences in peripheral vascular and cerebrovascular function between healthy and physically active premenopausal females and early and late postmenopausal females. Our findings contradict previous cross-sectional observations of vascular and cerebrovascular dysfunction across menopause. Longitudinal studies assessing vascular and cerebrovascular outcomes across the menopausal transition are warranted. The risk of cardiovascular and cerebrovascular disease increases in ageing females, coinciding with the onset of menopause. Differences in peripheral and cerebrovascular function across menopausal stages, however, are poorly characterized. The aim of this study was to compare peripheral and cerebrovascular function between healthy premenopausal (PRE), early (1-6 years after final menstrual period; E-POST) and late (>6 years after final menstrual period; L-POST) postmenopausal females. We also explored the association between reproductive hormones, NO bioavailability and cerebrovascular function. In 39 females (40-65 years of age), we measured arterial stiffness, brachial artery flow-mediated dilatation, and cerebrovascular reactivity (CVR) to hypercapnia in the middle (MCAv) and internal (ICA) carotid arteries. Follicle-stimulating hormone, estradiol, progesterone and plasma nitrate and nitrite concentrations were also measured. Years since final menstrual period (PRE, 0±0 years; E-POST, 3±1 years; L-POST, 11±4 years; P<0.001) and estradiol levels (PRE, 145.5±65.6 pgml-1 ; E-POSTm 30.2±81.2 pgml-1 ; L-POST, 7.7±11.3 pgml-1 ; P<0.001) were different between groups. All groups exceeded the guidelines for recommended physical activity. There were no group differences in blood pressure (P=0.382), arterial stiffness (P=0.129), flow-mediated dilatation (P=0.696) or MCAv CVR (P=0.442). The ICA CVR blood flow response was lower in PRE compared with L-POST (26.5±19.2vs. 47.8±12.6%; P=0.010), but after adjusting for age these differences were no longer present. Flow-mediated dilatation (r=0.313, P=0.105) and ICA CVR (r=-0.154, P=0.495) were not associated with the estradiol concentration. There were no associations between the estradiol concentration and NO bioavailability. These results suggest that in healthy, physically active early and late postmenopausal females, vascular and cerebrovascular function is generally well preserved.

Cerebral vascular function following the acute consumption of caffeinated artificially- and sugar sweetened soft drinks in healthy adults.

Chronic consumption of sugar- and artificially-sweetened beverages (SSB and ASB) are associated with an increased risk of stroke but it is unclear how acute consumption influences cerebral vascular function. Purpose: We hypothesized that: (1) acute consumption of SSB and ASB would augment dynamic cerebral autoregulation (dCA) and attenuate cerebral vascular reactivity to hypercapnia (CVRCO2) compared to water; and (2) dCA and CVRCO2 would be attenuated with SSB compared to ASB and water. Methods: Twelve healthy adults (age: 23 ± 2 years, four females) completed three randomized trials where they drank 500 ml of water, SSB (Mountain Dew®), or ASB (Diet Mountain Dew®). We measured mean arterial pressure (MAP), middle and posterior cerebral artery blood velocities (MCAv and PCAv), and end-tidal CO2 tension (PETCO2). Cerebral vascular conductance was calculated as cerebral artery blood velocity/MAP (MCAc and PCAc). Twenty min after consumption, participants completed a 5 min baseline, and in a counterbalanced order, a CVRCO2 test (3%, 5%, and 7% CO2 in 3 min stages) and a dCA test (squat-stand tests at 0.10 Hz and 0.05 Hz for 5 min each) separated by 10 min. CVRCO2 was calculated as the slope of the linear regression lines of MCAv and PCAv vs. PETCO2. dCA was assessed in the MCA using transfer function analysis. Coherence, gain, and phase were determined in the low frequency (LF; 0.07-0.2 Hz) and very low frequency (VLF; 0.02-0.07 Hz). Results: MCAv and MCAc were lower after SSB (54.11 ± 12.28 cm/s, 0.58 ± 0.15 cm/s/mmHg) and ASB (51.07 ± 9.35 cm/s, 0.52 ± 1.0 cm/s/mmHg) vs. water (62.73 ± 12.96 cm/s, 0.67 ± 0.11 cm/s/mmHg; all P < 0.035), respectively. PCAc was also lower with the ASB compared to water (P = 0.007). MCA CVRCO2 was lower following ASB (1.55 ± 0.38 cm/s/mmHg) vs. water (2.00 ± 0.57 cm/s/mmHg; P = 0.011) but not after SSB (1.90 ± 0.67 cm/s/mmHg; P = 0.593). PCA CVRCO2 did not differ between beverages (P > 0.853). There were no differences between beverages for coherence (P ≥ 0.295), gain (P ≥ 0.058), or phase (P ≥ 0.084) for either frequency. Discussion: Acute consumption of caffeinated SSB and ASB resulted in lower intracranial artery blood velocity and conductance but had a minimal effect on cerebral vascular function as only MCA CVRCO2 was altered with the ASB compared to water.

Cellular loci involved in the development of brain arteriovenous malformations.

Brain arteriovenous malformations (bAVMs) are abnormal vessels that are prone to rupture, causing life-threatening intracranial bleeding. The mechanism of bAVM formation is poorly understood. Nevertheless, animal studies revealed that gene mutation in endothelial cells (ECs) and angiogenic stimulation are necessary for bAVM initiation. Evidence collected through analyzing bAVM specimens of human and mouse models indicate that cells other than ECs also are involved in bAVM pathogenesis. Both human and mouse bAVMs vessels showed lower mural cell-coverage, suggesting a role of pericytes and vascular smooth muscle cells (vSMCs) in bAVM pathogenesis. Perivascular astrocytes also are important in maintaining cerebral vascular function and take part in bAVM development. Furthermore, higher inflammatory cytokines in bAVM tissue and blood demonstrate the contribution of inflammatory cells in bAVM progression, and rupture. The goal of this paper is to provide our current understanding of the roles of different cellular loci in bAVM pathogenesis.

Abstract P3136: Notch3 Deficiency Impairs Vascular Smooth Muscle Cell Contractility And Glymphatic Function In The Brain

While most cases of vascular dementia represent complex interactions between host genetics and environmental factors, mendelian forms of vascular dementia also exist. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian disease characterized by progressive vascular deterioration, cognitive deficits, and strokes. Mutations in the NOTCH3 receptor underlies the pathologies in CADASIL. NOTCH3 is primarily expressed in vascular smooth muscle cells (vSMCs) and its’ expression is critical for differentiation and functional integrity of arterial vSMCs, albeit through unclear mechanism(s). To elucidate the contribution of NOTCH3 in the maintenance of cerebral vascular architecture and function, we performed micro-computed tomography (micro-CT) on the brains of aged Notch3 -deficient animals. Micro-CT assessment of the cerebral vasculature architecture showed significant abnormalities including severe vessel dilation and tortuosity (dolicoectasia) of the middle cerebral artery and its branches in the Notch3 -/- compared to aged-match controls. To identify the molecular pathway from NOTCH3 dysregulation to the observed cerebral vascular dysfunction, we performed single-cell RNASeq on cerebral arteries isolated from young (4w) and old (104w) Notch3 -/- animals. Evaluation of the vSMC-specific transcriptomes indicated significant loss of proteins associated with muscle contraction and increased extracellular matrix production in animals that lack NOTCH3. Using a combination of immunofluorescence microscopy and in vitro functional assays, we confirmed that continued expression of Notch3 is a critical requirement for maintenance of vSMC contractile function. Impaired contractility also affected flow of cerebrospinal fluid in the parenchyma of Notch3 -/- . MRI and behavioral assessments were performed in the Notch3 -/- animals to elucidate the relationship between impaired vascular contractility to cognitive function. Taken together these findings link the molecular dysfunction of NOTCH3 through its regulation of vascular contractility and cerebral vessel architecture to altered neurological function and clarify the molecular pathways to cellular pathology of Notch3 driven dementias.

Cerebral endothelial cell derived small extracellular vesicles improve cognitive function in aged diabetic rats.

Small extracellular vesicles (sEVs) mediate cell-cell communication by transferring their cargo biological materials into recipient cells. Diabetes mellitus (DM) induces cerebral vascular dysfunction and neurogenesis impairment, which are associated with cognitive decline and an increased risk of developing dementia. Whether the sEVs are involved in DM-induced cerebral vascular disease, is unknown. Therefore, we studied sEVs derived from cerebral endothelial cells (CEC-sEVs) of aged DM rats (DM-CEC-sEVs) and found that DM-CEC-sEVs robustly inhibited neural stem cell (NSC) generation of new neuroblasts and damaged cerebral endothelial function. Treatment of aged DM-rats with CEC-sEVs derived from adult healthy normal rats (N-CEC-sEVs) ameliorated cognitive deficits and improved cerebral vascular function and enhanced neurogenesis. Intravenously administered N-CEC-sEVs crossed the blood brain barrier and were internalized by neural stem cells in the neurogenic region, which were associated with augmentation of miR-1 and –146a and reduction of myeloid differentiation primary response gene 88 and thrombospondin 1 proteins. In addition, uptake of N-CEC-sEVs by the recipient cells was mediated by clathrin and caveolin dependent endocytosis signaling pathways. The present study provides ex vivo and in vivo evidence that DM-CEC-sEVs induce cerebral vascular dysfunction and neurogenesis impairment and that N-CEC-sEVs have a therapeutic effect on improvement of cognitive function by ameliorating dysfunction of cerebral vessels and increasing neurogenesis in aged DM rats, respectively.

The acute effect of exercise intensity on peripheral and cerebral vascular function in healthy adults.

The acute effect of exercise intensity on cerebrovascular reactivity and whether this mirrors changes in peripheral vascular function have not been investigated. The aim of this study was to explore the acute effect of exercise intensity on cerebrovascular reactivity (CVR) and peripheral vascular function in healthy young adults (n = 10, 6 females, 22.7 ± 3.5 yr). Participants completed four experimental conditions on separate days: high-intensity interval exercise (HIIE) with intervals performed at 75% maximal oxygen uptake (V̇o2max; HIIE1), HIIE with intervals performed at 90% V̇o2max (HIIE2), continuous moderate-intensity exercise (MIE) at 60% V̇o2max and a sedentary control condition (CON). All exercise conditions were completed on a cycle ergometer and matched for time (30 min) and average intensity (60% V̇o2max). Brachial artery flow-mediated dilation (FMD) and CVR of the middle cerebral artery were measured before exercise, and 1- and 3-h after exercise. CVR was assessed using transcranial Doppler ultrasonography to both hypercapnia (6% carbon dioxide breathing) and hypocapnia (hyperventilation). FMD was significantly elevated above baseline 1 and 3 h following both HIIE conditions (P < 0.05), but FMD was unchanged following the MIE and CON trials (P > 0.33). CVR to both hypercapnia and hypocapnia, and when expressed across the end-tidal CO2 range, was unchanged in all conditions, at all time points (all P > 0.14). In conclusion, these novel findings show that the acute increases in peripheral vascular function following HIIE, compared with MIE, were not mirrored by changes in cerebrovascular reactivity, which was unaltered following all exercise conditions in healthy young adults.NEW & NOTEWORTHY This is the first study to identify that acute improvements in peripheral vascular function following high-intensity interval exercise are not mirrored by improvements in cerebrovascular reactivity in healthy young adults. High-intensity interval exercise completed at both 75% and 90% V̇o2max increased brachial artery flow-mediated dilation 1 and 3 h following exercise, compared with continuous moderate-intensity exercise and a sedentary control condition. By contrast, cerebrovascular reactivity was unchanged following all four conditions.

Acute Impact of JUUL Electronic Cigarette use on Cerebral Vascular Vasodilator Responsiveness

BackgroundCardiovascular disease is a major cause of death among cigarette smokers and is responsible for ~30% of heart disease related mortality in the U.S each year. Although cigarette smoking rates have declined in recent years, the use of electronic cigarettes (e‐cigarettes) continues to gain popularity in the U.S. and have generated widespread debate within the public health community, mostly due to the lack of scientific evidence regarding their safety and impact on health and behavior. The increasing rates of e‐cigarette use in the U.S have been largely attributed to the recent emergence of the high‐nicotine‐delivery pod‐based devices such as JUUL. Unlike e‐cigarettes, the literature surrounding the health impact of combustible cigarette smoking is well developed with overwhelming evidence of an adverse impact on various cardiovascular outcomes including impaired cerebral perfusion/vascular function. However, the impact of e‐cigarettes on cerebral vascular function remains to be elucidated, representing a major knowledge gap and research priority.HypothesisThis study tested the hypothesis that acute e‐cigarette vaping (JUUL) will impair cerebral vascular function as indexed by the cerebral vasodilatory responsiveness to a hypercapnic stimulus.MethodsA total of 16 adult smokers (mean age=25±5 yrs.) participated in this pilot study which occurred following an overnight fast. Cerebral vascular function was assessed as the hyperemic response to rebreathing‐induced hypercapnia before and ~45 min following a vaping session (10 puffs; 3s each, separated by 30s intervals). Heart rate (ECG), respiration (Pneumotrace), beat‐to‐beat blood pressure (Finometer), middle cerebral artery mean blood velocity (MCAv ‐ transcranial Doppler) and breath‐by‐breath end‐tidal carbon dioxide concentration (PETCO2‐ capnograph) were continuously measured. Cerebral vascular conductance index (CVCi) was calculated as MCAv / mean arterial pressure. Cerebral vasodilatory responsiveness was assessed as % increase in CVCi (%CVCi) during the highest common magnitude of hypercapnia achieved during the pre‐ and post‐vaping trials.ResultsAll CVCi data are reported at the highest common magnitude of hypercapnia achieved during the pre‐ and post‐vaping sessions (ΔPETCO2Pre: 13±2 mmHg, ΔPETCO2 Post: 12±2 mmHg; P=0.11). Cerebral vascular function/vasodilatory responsiveness, as assessed by the CVCi response to the hypercapnic challenge was significantly blunted following the vaping session (Pre: +52±25%, Post: +42±14%; P=0.04).ConclusionsOur preliminary results suggest that e‐cigarette vaping using JUUL acutely impairs cerebral vascular function as indexed by cerebral vasodilatory responsiveness to a hypercapnic challenge. These findings highlight the need for longitudinal studies to assess the long‐term impact of JUUL use on cerebral vascular function as well as other indices of cardiovascular health.

Hypoglycosylated Follistatin‐Like 1 Attenuates the Loss of Coronary and Cerebral Vascular Functional Capacity in Ossabaw Swine with Cardiometabolic Heart Failure with Reduced Ejection Fraction

Ischemic heart disease is a leading cause of death, often resulting from heart failure caused by myocardial infarction. Diabetic cardiomyopathy is increasingly problematic clinically, with the combination of metabolic syndrome and chronic inflammation greatly increasing the risk for both coronary and cerebral vascular disease. Follistatin‐like 1 (FSTL1) is a protein that, when non‐glycosylated, displays regenerative properties including pro‐angiogenic effects and prevention of abnormal vascular remodeling. Thus, the objective of the current study was to assess the therapeutic benefit of human recombinant non‐glycosylated FSTL1 protein on both coronary and cerebral vascular function in a pre‐clinical Ossabaw swine model of myocardial infarction (MI). We hypothesized FSTL1 would attenuate the development of coronary and cerebral vascular dysfunction in an experimental setting of cardiometabolic heart failure with reduced ejection fraction (HFrEF). Intact female Ossabaw swine (2 months old) were fed a Western Diet for 4 months to develop metabolic syndrome. At 6 months of age, animals were subjected to 90 minutes ischemia followed by reperfusion (I/R) to induce MI. One month post‐MI, ALZET osmotic pumps were implanted and either vehicle (MI group) or FSTL1 (MI+FSTL1 group) was delivered over two weeks, with terminal vascular experiments performed 2 months post‐MI. In vitroassessment of isolated coronary (n=5‐6 for infarct, border, and remote regions of the left ventricle; 139.5 ± 4.9 μm diameter) and cerebral (n=2‐6 for middle cerebral artery second order pial; 385.3 ± 18.7 μm diameter) arteriole function was examined using pressure myography. Dose response curves for: 1) U46619 (thromboxane A2 agonist); and 2) NS‐1619 (large‐conductance calcium‐activated potassium channel activator; BKCa) were conducted. A 2x2 ANOVA (Group X Dose) was used to determine significance at the p &lt; 0.05 level. Cardiometabolic HFrEF was indicated by a combined ejection fraction of 38 ± 2% and a fasting HOMA‐IR of 3.8 ± 0.4 (vs. 0.6 ± 0.1 historical control). In coronary arterioles, the NS‐1619 induced vasodilatory capacity was increased ~18‐fold in MI+FSTL1 animals relative to MI (100 ± 13% vs. 1832 ± 3% in MI and MI+FSTL1, respectively) in the remote region of the heart (interaction effect), but not the infarct nor border regions. In cerebral arterioles, the vasoconstrictor capacity in response to U46619 was increased ~2‐fold in MI+FSTL1 relative to MI animals (100 ± 19% vs. 213 ± 25% in MI and MI+FSTL1, respectively; interaction effect). In conclusion, FSTL1 partially attenuates the loss of functional capacity in both coronary and cerebral arterioles, demonstrating its potential to improve vascular function in an experimental setting of cardiometabolic HFrEF.

The Effects of Transcutaneous Vagal Nerve Stimulation on Dynamic Cerebral Autoregulation

PurposeTranscutaneous vagal nerve stimulation (tVNS) applied to the cervical branch of the vagus nerve is FDA‐approved to treat migraine and cluster headache. tVNS applied to the auricle branch of the vagus nerve (tVNSab) reduces muscle sympathetic nerve activity and improves cardiac parasympathetic activity after one session in healthy participants. Given the use of tVNS to treat cerebral disorders and its effects on autonomic function, we postulated that tVNSab might be beneficial for cerebral vascular function. We tested the hypotheses that tVNSab will increase resting middle cerebral artery blood flow velocity (MCAv) and improve dynamic cerebral autoregulation (dCA) during a repeated squat‐to‐stand procedure.MethodsSeven healthy participants (age: 20 ± 3 y; BMI:19 ± 7 kg/m2; 3 women) completed two randomized experimental visits on separate days. One visit consisted of tVNSab using a transcutaneous electrical nerve stimulation device (pulse width = 200 ms; pulse frequency = 30 Hz) with electrodes attached to the tragus of each ear. A time‐control visit (SHAM) was conducted with electrodes attached to the tragus but no current was applied. Mean arterial pressure (MAP; photoplethysmography), the partial pressure of end‐tidal carbon dioxide (PETCO2; capnography) and MCAv (transcranial Doppler ultrasound) were measured continuously. After 45 min of resting tVNS or SHAM, subjects performed a repeated squat‐to‐stand maneuver at a frequency of 0.05 Hz for 5 min while tVNSab or SHAM continued. Resting conductance values for the MCA (MCAc) were calculated as MCAv/MAP. MCA dCA was assessed during the squat‐to‐stand maneuver using spectral analyses to obtain coherence, gain, and phase values in the very low frequency (VLF) and low frequency (LF) bands. Spectral analysis gain was also assessed using normalized units (gainn), defined as beat to beat values divided by the mean value relative to changes in blood pressure. Data are presented as mean ± SD.ResultsThere were no differences between tVNSab and SHAM for MAP (tVNSab: 103 ± 8; SHAM: 102 ± 12 mmHg; P=0.41), PETCO2 (tVNSab: 35 ± 5; SHAM: 36 ± 2 mmHg; P=0.42), MCAv (tVNSab: 61.5 ± 9.2; SHAM: 58.7 ± 13.3 cm/s, P=0.36) or MCAc (tVNSab: 0.60 ± 0.08; SHAM: 0.59 ± 0.19 cm/s/mmHg, P=0.46) during baseline. There were no differences between conditions for coherence at VLF (tVNSab: 0.43 ± 0.14; SHAM: 0.45 ± 0.34; P=0.44) or LF (tVNSab: 0.65 ± 0.17; SHAM: 0.72 ± 0.13; P=0.06). Phase in the VLF (tVNSab: 0.35 ± 0.32; SHAM: 0.33 ± 0.36 rad; P=0.44) and LF (tVNSab: 0.28 ± 0.23; SHAM: 0.30 ± 0.16 rad; P=0.36) were not different. Gain (tVNSab: 0.56 ± 0.30; SHAM: 0.56 ± 0.54 cm/s/mmHg; P=0.50) and gainn (tVNSab: 0.99 ± 0.53; SHAM: 0.85 ± 0.84 %/mmHg; P=0.37) in the VLF were not different. However, gain (tVNSab: 0.76 ± 0.14; SHAM: 0.86 ± 0.17 cm/s/mmHg; P=0.02) and gainn (tVNSab: 1.22 ± 0.16; SHAM: 1.35 ± 0.23 %/mmHg; P=0.04) in the LF were lower during tVNSab.ConclusiontVNSab did not alter resting cerebral vascular responses. However, MCA LF gain was lower during tVNSab versus SHAM. These preliminary data indicate that dCA in a major intracranial cerebral artery might be improved during a single session of tVNSab. Further research regarding the influence of chronic tVNSab on cerebral vascular function is warranted.

Does Parkinson's Disease Affect Peripheral Circulation and Vascular Integrity?

Previous studies demonstrated that aging, neurodegeneration, and the level of physical activity are associated with vascular alterations. However, in Parkinson’s disease (PD) only cerebral vascular function has been investigated; instead, the contribution of PD on systemic vascular function and skeletal muscle circulation remains a matter of debate. In this study, the hyperemic response during the single passive leg movement test (sPLM) was examined at the level of the common femoral artery with an ultrasound Doppler system to assess systemic vascular function in 10 subjects with PD (PDG), compared with 10 aged‐sex and physically active matched healthy elderly (EHG), and 10 physically active young healthy individuals (YHG). Interestingly, femoral blood flow at rest was similar in PDG (64±15 mL min‐1 L‐1), EHG (44±8 mL min‐1 L‐1) and YHG (58±11 mL min‐1 L‐1). Our working hypothesis was that PDG would present an altered blood flow to the skeletal muscle, a reduced vascular function due to the pathology compared with the other groups. However, the sPLM‐hyperemic response appeared markedly lower in PDG and EHG compared to YHG (8.3±0.1 vs 9.8±0.8 vs 17±3 mL min‐1 L‐1; p &lt; 0.05) but the difference between PDG and EHG was negligible (p &gt; 0.05). The results of our study indicate that peripheral circulation and vascular function are not reduced in physically active patients with PD, suggesting that these vascular changes could resemble the physiological adjustments of aging, without any impact from the disease.

Contribution of Beta‐amyloid Accumulation to Cerebral Hypoperfusion in Alzheimer's Disease

Alzheimer’s Disease (AD) is an emerging global health care crisis. However, underlying mechanisms are not understood well enough to translate to precision medicine. There is increasing evidence suggesting that AD is associated with brain hypoperfusion. However, it is unclear whether amyloid‐beta (Aβ) accumulation is a cause or consequence of AD, and how it contributes to cerebral hypoperfusion. The present study examined if Aβ accumulation induces cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde (arteriole‐to‐capillary) and retrograde (capillary‐to‐arteriole) pathways in the TgF344‐AD rat model of Alzheimer's disease. We first confirmed that AD rats displayed hippocampal‐based cognitive dysfunction at 6 months of age using an eight‐arm water maze. We then found that AD rats exhibited impaired myogenic response (MR) of middle cerebral arteries (MCAs) and penetrating and parenchymal arterioles (PAs) two months earlier than the onset of cognitive deficits using a Living System pressure myograph. AD rats displayed poor surface and deep cortical cerebral blood flow (CBF) autoregulation recorded by laser Doppler flowmetry, and reduced functional hyperemic response induced by whisker stimulation. Moreover, cell contractile capabilities, detected by collagen gel based‐cell contraction kit, were reduced in Aβ‐treated cerebral VSMCs isolated from F344 rats, similar as seen in VSMCs isolated from AD rats. Furthermore, we found that the productions of reactive oxygen species (ROS) and mitochondrial superoxide in cerebral VSMCs isolated from AD rats were elevated using DHE staining and MitoSOX staining. Moreover, AD cells exhibited reduced mitochondrial respiration and ATP production detected by the Seahorse Cell Mito Stress Test kit. AD cerebral VSMCs also exhibited disrupted actin cytoskeleton and contractile units utilizing immunohistochemistry. Oxidative stress, mitochondrial dysfunction, and actin cytoskeleton disorganization are all factors that are associated with the reduced contractile capabilities of cerebral VSMCs mediated MR and CBF autoregulation. In other studies, we found that capillary endothelial cell‐derived inward rectifier potassium (Kir2.1) activity, which is responsible for retrograde CBF regulation, was reduced in the brain of AD rats using Western blot. PAs with capillaries isolated from AD rats dilated to a lesser degree than WT rats in response to moderately elevated extracellular K+ (10 mM) applied to capillaries. Inhibition of Kir2.1 channels with ML133 diminished the vasodilatory response to a greater extent in WT rats. These findings indicate that Aβ accumulation is associated with cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde and retrograde pathways and provide novel insight into the vascular contribution to AD.

Low vs. High Wattage Vaping during Pregnancy Influences Vascular Function in Rat Offspring

Electronic cigarettes (e‐cigs) are being marketed as a healthier alternative to traditional cigarettes, yet the health consequences of e‐cig usage (also called vaping) are still being investigated. E‐cigs are easily customized for user preferences. For example, choice of flavors, nicotine concentration, and/or temperature (i.e. wattage) used to combust the e‐liquid can be selected in many devices. Emerging evidence suggest vaping during pregnancy impairs cerebral vascular function in rodent offspring. In this study, we sought to investigate the potential effects of changes in e‐cig device wattage (i.e. 5 watts vs 30 watts) with maternal vaping during pregnancy of vascular function in postnatal life of offspring. METHODS: Adult female Sprague Dawley rats were time‐mated to allow for maternal e‐cig exposure beginning on gestation day 2 until birth. Maternal vaping occurred for 1 h/day, 5 days/wk using a whole‐body chamber system. E‐cig aerosol was generation using D19 Joyetech atomizer with nicotine‐free (0 mg/mL) 50:50 VG:PG e‐liquid without flavoring. Puff topology was 83 ml with 5‐sec puff duration. Pregnant dams were randomly assigned to control (air‐exposed), 5 watt or 30‐watt exposure groups. Rat offspring (n=2/dam) were studied at 30‐, 90‐, and 180‐days after birth, where in vivo pulse wave velocity (an index of arterial stiffness) was assessed using VisualSonics Vevo 2100 ultrasound, thereafter animals were euthanized and thoracic aortas were excised, cleaned, and cut into 2mm rings for wire myography (DMT, AD instruments). Aortic rings were mounted and warmed in aerated Krebs‐Henseleit buffer solution. Vessel reactivity was measured using serial dilutions of methacholine [MCh 10‐9to 10‐5M] and sodium nitroprusside [SNP 10‐9 to 10‐5 M] to assess endothelial‐dependent vasodilation (EDD) and endothelium‐independent vasodilation (EID), respectively. RESULTS: At the 30‐days, max aortic EDD was not different between either 5W (79±17%, mean±SD) or 30W (86±4%) groups compared to controls (88±4%)(p&gt;0.36). At 90‐days, max aortic EDD was lower with 30W (58±18%, p&lt;0.001), but not 5W (78±4%, p=0.11) compared to controls (95±6%). Carotid PWV was elevated in 5W (3.49 m/s) and 30W (3.83 m/s) groups compared to controls (2.98 m/s, p&lt;0.05) suggesting 17‐29% increase in arterial stiffness. At 180 days, max aortic EDD was also lower with 30W (75±12%, p&lt;0.01), but not 5W (81±9x%, p=0.11) compared to controls (100±10%). Carotid PWV was elevated further in 5W (3.96 m/s) and 30W (4.29 m/s) groups compared to controls (3.13 m/s, p&lt;0.05) revealing 27‐37 % increase in arterial stiffness. Maximal aortic EID response (to SNP) was not different by wattage group or age. CONCLUSIONS: These findings show that e‐cig device power used during maternal vaping plays a role in increasing arterial stiffness and blunting EDD vascular function in the postnatal life of offspring with effects worsening with age. These data suggest vaping during pregnancy is not safe and has long‐lasting consequences to vascular health of progeny.

In vivo whole brain microvascular imaging in mice using transcranial 3D Ultrasound Localization Microscopy

SummaryBackgroundNon-invasive high-resolution imaging of the cerebral vascular anatomy and function is key for the study of intracranial aneurysms, stenosis, arteriovenous malformations, and stroke, but also neurological pathologies, such as degenerative diseases. Direct visualization of the microvascular networks in the whole brain remains however challenging in vivo.MethodsIn this work, we performed 3D ultrafast ultrasound localization microscopy (ULM) using a 2D ultrasound matrix array and mapped the whole-brain microvasculature and flow at microscopic resolution in C57Bl6 mice in vivo.FindingsWe demonstrated that the mouse brain vasculature can be imaged directly through the intact skull at a spatial resolution of 20 µm and over the whole brain depth and at high temporal resolution (750 volumes.s−1). Individual microbubbles were tracked to estimate the flow velocities that ranged from 2 mm.s−1 in arterioles and venules up to 100 mm.s−1 in large vessels. The vascular maps were registered automatically with the Allen atlas in order to extract quantitative vascular parameters such as local flow rates and velocities in regions of interest.InterpretationWe show the potential of 3D ULM to provide new insights into whole-brain vascular flow in mice models at unprecedented vascular scale for an in vivo technique. This technology is highly translational and has the potential to become a major tool for the clinical investigation of the cerebral microcirculation.FundingThis study was supported by the European Research Council under the European Union's Seventh Framework Program (FP/2007-2013) / ERC Grant Agreement n° 311025 and by the Fondation Bettencourt-Schueller under the program “Physics for Medicine”. We acknowledge the ART (Technological Research Accelerator) biomedical ultrasound program of INSERM.

Does Parkinson's disease affect peripheral circulation and vascular function in physically active patients?

Previous studies demonstrated that aging, neurodegeneration, and the level of physical activity are associated with vascular alterations. However, in Parkinson's disease (PD) only cerebral vascular function has been investigated; instead, the contribution of PD on systemic vascular function and skeletal muscle circulation remains a matter of debate. In this study, the hyperemic response during the single passive leg movement test (sPLM), largely nitric oxide dependent, was examined at the level of the common femoral artery with an ultrasound Doppler system to assess systemic vascular function in 10 subjects with PD (PDG), compared with 10 aged-sex and physically active matched healthy elderly (EHG), and 10 physically active young healthy individuals (YHG). Interestingly, femoral blood flow at rest, normalized for the thigh volume, was similar in PDG (64 ± 15 mL·min-1·L-1), EHG (44 ± 8 mL·min-1·L-1), and YHG (58 ± 11 mL·min-1·L-1, all P values > 0.05). The sPLM-induced hyperemic response appeared markedly lower in PDG and EHG compared with YHG (8.3 ± 0.1 vs. 9.8 ± 0.8 vs. 17.3 ± 3.0 mL·min-1·L-1; P < 0.05) but the difference between PDG and EHG was negligible (P > 0.05). The results of our study indicate that peripheral circulation and vascular function are not reduced in physically active patients with PD, suggesting that these vascular changes could resemble the physiological adjustments of aging, without any impact from the disease.NOTE & NOTEWORTHY Our study verified an intact peripheral circulation in patients with Parkinson's disease (PD). However, using the single passive leg movement, we observed a similar reduction of the vascular integrity in physically active patients and matched elderly, compared with young, likely induced by aging but independent on the pathology. This comparable effect confirmed that the disease, at early stage, with a dynamic lifestyle does not worsen the vascular system but reveals the cardinal symptoms of PD.

Young, non-Hispanic Black men and women exhibit divergent peripheral and cerebral vascular reactivity.

What is the central question of the study? Do peripheral and cerebral vascular function differ between young non-Hispanic Black men and women? What is the main finding and its importance? The non-Hispanic Black women in this study presented greater peripheral conduit artery and cerebrovascular reactivity, yet similar peripheral microvascular function relative to the non-Hispanic Black men. These preliminary findings suggest that young Black women and men possess divergent vascular function, possibly contributing to the unique non-Hispanic Black sex differences in cardiovascular and cerebrovascular diseases. In the USA, cardiovascular and cerebrovascular diseases remain more prominent in the non-Hispanic Black (BL) population relative to other racial/ethnic groups. Typically, sex differences emerge in the manifestation of these diseases, though these differences may not fully materialize in the BL population. While numerous mechanisms are implicated, differences in vascular function likely contribute. Research has demonstrated blunted vasodilatation in several vascular regions in BL versus non-Hispanic White individuals, though much of this work did not assess sex differences. Therefore, this study aimed to ascertain if indices of vascular function are different between young BL women (BW) and men (BM). Eleven BW and 15BM (22 (4) vs. 23 (3) years) participated in this study. Each participant underwent testing for brachial artery flow-mediated dilatation (FMD), post-occlusive reactive hyperaemia and cerebral vasomotor reactivity during rebreathing-induced hypercapnia. BW exhibited greater adjusted FMD than BM (P<0.05 for all), but similar or lower reactive hyperaemia when assessed as blood velocity (P>0.39 for all) or blood flow reactivity (P<0.05 for all), respectively. Across a range of hypercapnia, BW had greater middle cerebral artery blood velocity and cerebrovascular conductance index than BM (P<0.001 for both). These preliminary data suggest that young BW have greater vascular function relative to young BM, though this was inconsistent across different indices. These findings provide insight into the divergent epidemiological findings between BM and BW. Further research is needed to elucidate possible mechanisms and relate these physiological responses to epidemiological observations.

Six nights of sleep extension increases regional cerebral oxygenation without modifying cognitive performance at rest or following acute aerobic exercise.

Long sleep durations (≥540min) are associated with poor cognitive performance in ageing adults, but the underlying cause is unclear. The aim of this study was to investigate the effect of extended sleep on cognitive performance and cerebral vascular function before and then after aerobic exercise. In all, 12 adults completed 6nights of 8- (control) and 10+-h (sleep extension) time in bed in a randomised, crossover experiment. Sleep was measured using wrist actigraphy. On the last day of each time in bed protocol, participants performed three bouts of brisk walking. Sustained attention, spatial rotation ability, mental flexibility, and working memory were assessed, while prefrontal oxygen saturation index (ΔTSI) was measured using near-infrared spectroscopy. A two-way repeated-measures analysis of variance (time in bed×before/after exercise) was used for statistical analysis. Average sleep duration was longer following sleep extension as compared to control, at a mean (SD) of 551(16) versus 428(20)min (p&lt;0.001). Sleep extension did not alter cognitive performance as compared to control, but increased ΔTSI during tests of spatial rotation ability (main effect for time in bed, p=0.03), mental flexibility (p=0.04), and working memory (p&lt;0.01). Cognitive performance was improved (main effect for exercise, p&lt;0.05) following brisk walking for all cognitive domains except sustained attention with no interaction with time in bed. In summary, 6nights of extended time in bed accompanied by long sleep durations does not impair cognitive performance at rest or alter the positive effect of acute aerobic exercise on cognition but may increase frontal cerebral oxygenation during cognitive functioning.

Pre-stroke Physical Activity and Cerebral Collateral Circulation in Ischemic Stroke: A Potential Therapeutic Relationship?

Favorable cerebral collateral circulation contributes to hindering penumbral tissue from progressing to infarction and is associated with positive clinical outcomes after stroke. Given its clinical importance, improving cerebral collateral circulation is considered a therapeutic target to reduce burden after stroke. We provide a hypothesis-generating discussion on the potential association between pre-stroke physical activity and cerebral collateral circulation in ischemic stroke. The recruitment of cerebral collaterals in acute ischemic stroke may depend on anatomical variations, capacity of collateral vessels to vasodilate, and individual risk factors. Physical activity is associated with improved cerebral endothelial and vascular function related to vasodilation and angiogenic adaptations, and risk reduction in individual risk factors. More research is needed to understand association between cerebral collateral circulation and physical activity. A presentation of different methodological considerations for measuring cerebral collateral circulation and pre-stroke physical activity in the context of acute ischemic stroke is included. Opportunities for future research into cerebral collateral circulation, physical activity, and stroke recovery is presented.