bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ligustilide activates Nrf2/HO‐1 induction, NO synthesis and ameliorates vascular inflammation in HUVECs
Authors: Choi Eun Sik , Yoon Jung Joo , Namgung Seung , Jeong Da Hye , Kim Hyun Ju , Lee Yun Jung , Kang Dae Gill , Lee Ho Sub 
Published: November 2023

(Z)‐ligustilide is a bioactive phthalide derivative isolated from Cnidii Rhizoma (Cnidium officinale, rhizome) and Angelicae Gigantis Radix (Angelica gigas Nakai, root). Vascular endothelium is a central spot in developing cardiovascular diseases and chronic vascular inflammation results in atherosclerosis development. We investigated anti‐inflammatory effects of ligustilide against TNF‐α, and whether ligustilide can activates Nrf2/HO‐1 induction, intracellular NO synthesis in endothelial cells. Ligustilide significantly suppressed adhesion of HL‐60 monocyte to HUVECs via suppressing expression of VCAM‐1, ICAM‐1, and E‐selectin against TNF‐α. Also, ligustilide significantly inhibited ROS production and IκB‐α phosphorylation, and it leaded to suppression of NF‐κB activation. Furthermore, ligustilide up‐regulated induction of HO‐1 via Nrf2 nuclear translocation and synthesis of intracellular NO in HUVECs. Present study demonstrates that ligustilde has vascular protective potential and it might prevents developing cardiovascular complications such as thrombosis or atherosclerosis.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2008‐0062484).
Mechanisms of Vasodilatory Effects of Total Flavonoids from Euphorbia humifusa in Rat Aorta
Authors: Ji Xiao Wei , Wu Bo , Zhou Zi Qi , Kang Dae Gill , Lee Ho Sub , Cho Kyung Woo , Jin Song Nan , Wen Jin Fu 
Published: November 2023

Euphorbia humifusa (EH) is, rich in flavonoids, used for treating bacillary dysentery and enteritis in many Asian countries. It is noteworthy that the beneficial actions of EH, such as inhibiting inflammation, antioxidation, enhancing immunity and lowering blood pressure, might be mainly attributed to its abundant flavonoids. However, the effects of total flavonoids of EH (TFEH) on the vascular function and its pharmacological mechanisms of action have not been studied. The aim of the present study was to evaluate the vascular effects of TFEH and its action mechanisms in rats. The vasoactive effect of TFEH and its underlying mechanisms in rat thoracic aortas were investigated using the organ bath system. TFEH induced a concentration‐dependent vasorelaxation in endothelium‐intact (+E) aortic rings, which was abolished by the removal of endothelium. The nitric oxide synthase inhibitor L‐NAME and the soluble guanylate cyclase inhibitor ODQ significantly attenuated the endothelium‐dependent vasorelaxation of TFEH. However, inhibition of cyclooxygenases with indomethacin had no effects on the TFEH‐induced vasorelaxation. Extracellular Ca2+ depletion, inhibition of L‐type Ca2+ channels with diltiazem and modulators of the store‐operated Ca2+ entry (SOCE), Gd3+ and 2‐aminoethyl diphenylborinate markedly attenuated the TFEH‐induced vasorelaxation in +E vessels. Wortmannin, an inhibitor of Akt, significantly attenuated the TFEH‐induced vasorelaxation in +E vessels. Furthermore, K+ channel blockers, such as a non‐selective KCa channels blocker tetraethylammonium and KATP channel blocker glibenclamide, and inhibitors of muscarinic and adrenergic receptors had no significant effects on the vasorelaxation. These data demonstrate that TFEH induces vasorelaxation through activation of endothelium‐dependent two‐step signaling: first is an activation of the Akt‐ and Ca2+‐eNOS‐NO signaling in the endothelial cells and then subsequent stimulation of the NO‐soluble guanylyl cyclase‐cGMP signaling in the vascular smooth muscle cells.Support or Funding InformationThis work was supported by research grants from the National Natural Science Foundation of China (Nos. 81270920, 31571175), the Natural Science Foundation of Shandong Province (No. ZR2015HM037), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2008‐0062484).
The Functional Contribution Of Myoendothelial Feedback To Arterial Tone Is Determined By The Nature Of The Vasoconstricion
Authors: Kerr Paul M , Wei Ran , Lunn Stephanie E , Gust Stephen L , Classen Boyd , Murphy Timothy V , Sandow Shaun L , Plane Frances 
Published: November 2023

Constriction of resistance arteries in response to global application of agonists is modulated by activation of the endothelium via myoendothelial feedback. Recent evidence supports a model of myoendothelial feedback in which generation of localized InsP3‐dependent Ca2+ transients leads to activation of intermediate conductance Ca2+‐activated K+ (IKCa) channels to hyperpolarize the endothelium. We have now investigated the functional contribution of this pathway to limiting responses to two physiologically important vasoconstrictor stimuli, activation of sympathetic nerves and increases in intravascular pressure. In isolated segments of rat mesenteric resistance artery mounted in a wire or pressure myograph, pharmacological inhibition of IKCa channels significantly potentiated increases in tone elicited by global application agonists such as noradrenaline, but did not significantly alter increases in tone elicited by stimulation of sympathetic perivascular nerves, or myogenic reactivity elicited by step‐wise increases in intravascular pressure. Similarly, in the endothelium‐intact perfused mesenteric bed, blockers of IKCa channels enhanced vasoconstriction to exogenous noradrenaline but had no effect on nerve‐evoked vasoconstriction. However, the influence of the endothelium on responses to sympathetic nerve stimulation was inhibited by blockers of nitric oxide signaling and by inhibition of small conductance Ca2+‐activated K+ (SKCa) channels. These data demonstrate that the contribution of myoendothelial feedback to endothelium‐dependent modulation of tone is determined by the stimulus for smooth muscle contraction. Although activated by global application of contractile agonists, the myoendothelial feedback pathway does not appear to play a significant role in modulating myogenic reactivity or nerve‐evoked responses in resistance arteries. Furthermore, in the intact mesenteric vascular bed, under conditions of constant flow, increases in shear stress rather than myoendothelial feedback, may be the predominant stimulus for engagement of the endothelium to oppose nerve‐evoked vasoconstriction.Support or Funding InformationSupported by a grant‐in‐aid from the Heart and Stroke Foundation of Alberta, Nunavut and the North West Territories to FP (G130003076)
Vasoactivity of the Vasculature Directly Supplying the Rat Sciatic Nerve
Authors: Williams Elise , Klein Amanda Taylor , Jackson Dwayne N , Twynstra Jasna 
Published: November 2023

ObjectivesThe purpose of this study was to determine the vasoactivity of the vasculature directly supplying the sciatic nerve in response to phenylephrine (PE) and acetylcholine (ACh) using plasma fluorescence and intravital microscopy.MethodsPE (10−4M, n=6) and ACh (10−4M, n=9) were applied to an exposed sciatic nerve in an anesthetized Sprague Dawley rat model (PE: 321.6±11.7g, ACh: 307.56±41.57g). A fluorescent dye, FITC (0.3 ml at 5%), was infused via a jugular catheter to fluoresce the plasma stream, while intravital microscopy was used to visualize the plasma stream through the vessels running directly over the sciatic nerve. Each vasoactive agent was topically applied over the sciatic nerve for 6 minutes. Measurements were taken at baseline (immediately prior to drug application), 2 minutes, 4 minutes and 6 minutes after the start of drug application, and finally at 4 minutes after PE or ACh application was stopped (recovery). Maximal diameter was achieved via application of 10−4M of Sodium Nitroprusside (SNP). Data are expressed as mean ± standard error.ResultsFollowing PE and ACh application, mean arterial pressure (baseline PE: 105.6±11.1mmHg; PE: 102.0±9.9mmHg, baseline ACh: 100.8±4.1mmHg, ACh: 100.2±4.6mmHg) was not affected. PE application resulted in a decreased diameter of the plasma stream (maximal change in diameter: −5.8±1.9um), while ACh application did not result in changes in diameter (maximal change in diameter: 1.5±0.7um). Maximal diameter in response to SNP was not significantly different from the baseline diameter (Baseline: 19.36±6.62um, SNP: 19.80±7.01um)ConclusionPE application resulted in a vasoconstriction of the vessels directly supplying the sciatic nerve, while application of ACh or SNP failed to produce significantly vasodilation. Overall, the vessels supplying the sciatic nerve appeared to be maximally dilated at baseline, which may explain the lack of dilation in response to ACh or SNP.Support or Funding InformationThis study was supported by Brescia University College Research Grant.
Acid‐Sensing Ion Channels: Mediator of Cerebrovascular Responses to CO2
Authors: Faraci Frank , Taugher Rebecca , Fan Rong , Wemmie John 
Published: November 2023

Because normal brain function is critically dependent on cerebral blood flow (CBF), insufficient CBF contributes to neurological dysfunction and degeneration. Carbon dioxide (CO2), via effects on local acidosis, is one of the most potent regulators of CBF. Although a role for nitric oxide (NO) in intermediate signaling has been implicated, mechanisms that initiate CO2 induced‐vasodilation remain unclear. Acid‐sensing ion channel‐1A (ASIC1A) is a proton‐gated cation channel that is activated by extracellular acidosis. Based on work that implicated ASIC1A in the amygdala and stria terminalis in CO2‐ and acid‐evoked behavior, we hypothesized that ASIC1A might also mediate microvascular response to CO2. To test this hypothesis, we genetically and pharmacologically manipulated ASIC1A and assessed effects on CO2‐induced dilation of small cerebral arterioles in vivo. Genetic deficiency in ASIC1A (Asic1a−/−) or local treatment with psalmotoxin (an ASIC inhibitor) in Asic1a+/+ mice eliminated the majority of the effect of 5 or 10% CO2 on arteriolar diameter (P<0.05). Vasodilator effects of acetylcholine, which acts via endothelial NO synthase were unaffected, suggesting a non‐vascular source of NO was key for CO2 responses. We then hypothesized that neurons may be the cell type through which ASIC1A influences microvessels. In mice in which Asic1a was specifically disrupted in neurons, effects of CO2 on arteriolar diameter were also greatly attenuated. To further explore a role for ASIC1A in the regulation of NO production, we measured NO concentrations in whole brain lysates immediately after exposure to CO2. We found that 10% CO2 induced NO production in wild‐type mice, but not in mice lacking Asic1a globally or specifically in neurons. Together, these data are consistent with a model wherein activation of neuronal ASIC1A is critical for CO2‐induced NO production and vasodilation. With these findings, ASIC1A emerges as major regulator of microvascular tone in brain.Support or Funding InformationThis work was supported by the NIH, the Department of Veterans Affairs, and the Fondation Leducq.
Multiple Sclerosis Alters Dynamic Cerebral Autoregulation during Heat Stress
Authors: Allen Dustin Ryan , Huang Mu Ryan , Purkayastha Sushmita , Brothers Robert Matthew , Davis Scott L 
Published: November 2023

Multiple sclerosis (MS) is a neurological disease marked by demyelination within the central nervous system that results in individuals with MS experiencing a myriad of symptoms, including cognitive dysfunction and orthostatic dizziness. Adding complexity, many individuals with MS (60–80%) experience temporary worsening of their symptoms upon increases in core temperature (Tcore), an occurrence known as Uhthoff's phenomenon. This study tested the hypotheses that individuals with MS: 1) have impaired cerebral autoregulation under normothermic baseline conditions, and 2) have exacerbated impairments in cerebral autoregulation as a result of a passive heat stress compared to healthy controls (CON). Seven subjects with relapsing‐remitting MS (age: 44±7 yrs; height: 174±9 cm; weight: 74±17 kg) and 7 matched healthy controls (CON; age: 44±6 yrs; height: 176±11 cm; weight: 81±14 kg) were outfitted in a tube‐lined water perfusion suit in which they were exposed to a normothermic baseline (NT: 34 °C circulating water) condition for 10 minutes followed by a ~60‐minute whole‐body heat stress (WBH: 48 °C circulating water) until a 0.8 °C increase in Tcore was achieved. Continuous measurements of mean middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasonography) and mean arterial pressure (MAP; finger photopleythsmography) were taken throughout each thermal condition. Transfer function analysis of beat‐to‐beat fluctuations in MAP and MCAv was used to quantify dynamic cerebral autoregulation (dCA) during NT and WBH. All data from transfer function analyses were examined at very low frequency (VLF: 0.02–0.07 Hz), low frequency (LF: 0.07–0.20 Hz), and high frequency (HF: 0.20–0.30 Hz) ranges. Estimates of coherence exceeded 0.5 at LF and HF during NT, and all frequencies during WBH. Contrary to our hypothesis, LF phase (MS: 0.37±0.20 vs CON: 0.55±0.37 radians, p=0.29) and LF gain (MS: 0.83±0.21 vs CON: 0.89±0.12 cm/s/mmHg, p=0.52) were similar during NT. No differences in LF phase during WBH (MS: 0.73±0.30 vs CON: 0.66±0.30 radians, p=0.66). However, differences in LF gain were observed between groups following WBH (MS: 1.26±0.47 vs CON: 0.79±0.21 cm/s/mmHg, p=0.03). These preliminary data demonstrate a negative impact on estimates of transfer function gain that manifest with increases in Tcore, likely indicating MS impairments in dynamic cerebral autoregulation during heat stress.Support or Funding InformationSupported by NIH (R15HL11722401) and NMSS (RG4696A3/2) grants.
Elevated Cardiorespiratory Fitness is Associated with Blunted Cerebral Pressure‐Flow Relationships
Authors: Brassard Patrice , Paquette Myriam , Le Blanc Olivier , Malenfant Simon , Rahimaly Kevan , Lucas Samuel JE , Bailey Damian M 
Published: November 2023

There appears to be a “hemodynamic paradox” associated with elevated cardiorespiratory fitness; in that it has a differential impact on cerebral blood flow and orthostatic tolerance. A reduction in orthostatic tolerance with high cardiorespiratory fitness may be related to a blunted cerebral pressure‐flow relationship during rapid changes in blood pressure, and not only a consequence of inadequate cerebral perfusion. However, research on how cardiorespiratory fitness influences cerebral pressure‐flow relationships during rapid changes in blood pressure, and the consequences for orthostatic tolerance remain equivocal. Mean arterial pressure (MAP; finger photoplethysmography) and middle cerebral artery flow velocity (MCAv; transcranial Doppler ultrasound) were continuously monitored in 19 male endurance athletes (V̇O2max: 56±5 mL·kg−1·min−1) and 8 inactive/moderately active control participants (39±5 mL·kg−1·min−1, P<0.01). Orthostatic tolerance was assessed by the prevalence of presyncope during a 20‐min 70° head‐up tilt. Cerebral pressure‐flow relationships were assessed by: [1] the time delay before onset of regulation (increase in the cerebrovascular conductance index (MCAvmean/MAP)) and [2] rate of regulation, after transient hypotension induced by bilateral thigh‐cuff release and sit‐to‐stand, and transfer function analysis (TFA) of blood pressure and MCAv responses during [3] spontaneous and [4] forced oscillations induced via 5‐min of repeated squat‐stand maneuvers at both 0.05 and 0.10 Hz. Prevalence of presyncope was not different between groups (p=0.41). The time delay before onset of regulation tended to be longer in athletes compared to controls after thigh‐cuff deflation (p=0.11) and prolonged after sit‐to‐stand (3.2 ± 1.6 vs. 1.4 ± 1.1 s; p=0.01), and the latter correlated with V̇O2max (r=0.46, p=0.03). Rate of regulation was similar between groups irrespective of the technique employed. Athletes had lower TFA phase in the low frequency (p<0.01) range and higher TFA gain during 0.1 Hz squat‐stand compared to controls (p=0.01). Metrics describing cerebral pressure‐flow relationships did not correlate with orthostatic tolerance. These results indicate an attenuated ability of the cerebral vasculature to react to slow rhythmical oscillations as well as rapid and large changes in blood pressure in fit individuals. However, these functional cerebrovascular adaptations do not influence orthostatic tolerance.Support or Funding InformationThe present study was funded by the Ministère de l'Education, du Loisir et du Sport du Québec, and the Foundation of the Institut universitaire de cardiologie et de pneumologie de Québec
The Effect of Alcohol Exposure in Utero on The Cerebral Circulation
Authors: Cananzi Sergio , Mayhan William 
Published: November 2023

Fetal alcohol spectrum disorders (FASD) comprises several syndromes and permanent birth defects caused by in utero exposure to alcohol. FASD is linked to growth deficiencies, craniofacial abnormalities, and central nervous system damage. Although there is some evidence that FASD might be linked to cerebral vascular dysfunction in the fetal stage of development and into adulthood, very few studies have examined this possibility. The overall goal of our studies is to examine the influence of in utero exposure to alcohol on the cerebral microcirculation. We speculated that in utero exposure to alcohol would have a negative influence on cerebral blood vessels and this might be linked to neurological deficits observed in adults that suffer from FASD. The mechanism by which in utero exposure to alcohol affects brain development is not clear, but it may be related to the effect of alcohol on oxidative stress. Thus, our central hypothesis is that in utero exposure to alcohol produces an increase in oxidative stress to impair reactivity of cerebral arterioles and increase brain damage following cerebral ischemia/reperfusion. We suggest our studies will help fill a void in our understanding of the influence of in utero exposure to alcohol on cerebral blood vessels and how these factors may influence the deficits observed in individuals affected by FASD.Support or Funding InformationMalcolm Feist Cardiovascular Fellowship, LSUHSC Shreveport LA.
Endothelial Pannexin1 can regulate cerebral myogenic tone development and severity of ischemic stroke
Authors: Good Miranda Elizabeth , Bacon Hannah M , Eucker Stephanie A , Lang Susan M , Butcher Joshua T , Johnson Tyler J , Li Jun , Zuo Zhiyi , Isakson Brant E 
Published: November 2023

Pannexin1 (Panx1) regulates adrenergic dependent vasoconstriction in peripheral arterioles; however, unlike peripheral arterioles, regulation of cerebral arteriole vasoconstriction is predominantly due to myogenic tone. Because ATP can elicit potent vasoconstriction of cerebral arterioles, we hypothesized that ATP release from Panx1 channels was involved in the development of myogenic tone of cerebral arterioles. Initially we found that myogenic tone in posterior cerebral arteries (PCAs) from wildtype mice was significantly inhibited when arterioles were treated with apyrase. Next we treated PCAs with pannexin pharmacological inhibitors (carbenoxolone, 10Panx1, and spironolactone), which also significantly reduced the development of myogenic tone. Spironolactone, which we found does not inhibit Cx43 hemichannels, had no effect on myogenic tone development in peripheral arterioles (i.e, third order mesenteric arterioles). Next we used a genetic approach to pannexin inhibition and used either mice lacking Panx1 in smooth muscle cells (SMC; SMC‐Cre Panx1fl/fl) or endothelial cells (EC; EC‐Cre Panx1fl/fl). The myogenic tone was not altered in the SMC‐Cre Panx1fl/fl mice, but was significantly reduced in the EC‐Cre Panx1fl/fl mice. In line with the spironolactone data, myogenic tone development in peripheral arterioles of EC‐Cre Panx1fl/fl mice was not different. Consistent with these data, we could detect no difference in blood pressure of EC‐Cre Panx1fl/fl mice compared to control mice. Since myogenic tone regulates the cerebral blood flow and has been suggested to play a role in stroke outcome, we investigated the stroke infarct volume in both SMC‐Cre Panx1fl/fl and EC‐Cre Panx1fl/fl mice. Experimentally we used a 90 min intra‐luminal filament occlusion to induce ischemia of the middle cerebral artery followed by 24 hour reperfusion upon removal. We found that stroke infarct volume was significantly reduced in EC‐Cre Panx1fl/fl mice, while SMC‐Cre Panx1fl/fl mice showed no protection. Since EC‐Cre Panx1fl/fl mice show reduced leukocyte rolling and adhesion following TNFα‐stimulation, we examined if these mice also demonstrate reduced infiltration of leukocytes. Preliminary data indicate that EC‐Cre Panx1fl/fl mice have reduced overall number of leukocytes in the ischemic hemisphere compared to control mice. Our data demonstrate that Panx1 in endothelium may regulate ischemic stroke outcome, possibly through myogenic tone of cerebral arterioles and/or the extent of leukocyte infiltration.Support or Funding InformationFunding: HL088554, HL120840, HL007284, HL131399.
Integrative Physiology of Brain Perfusion During Extreme Chemoreflex Manoeuvers
Authors: Shoemaker J. Kevin , Barak Otto F. , Badrov Mark Kevin , Shoemaker Leena N. , Matushewski Bradley Kevin , Mijacika Tanja , Lojpur Mihajlo , Drvis Ivan , Dujic Zeljko 
Published: November 2023

Both cerebral perfusion pressure (CPP) and vascular conductance (CVC) contribute to blood flow. Yet, rarely are these factors considered in cerebrovascular reactivity studies, in favour of the change in mean flow velocity (MFV) for a given dilatory stimulus such as carbon dioxide, an approach that can ignore the potential contributions of CPP. We tested the hypothesis that both CVC and CPP facilitate the increase cerebral perfusion during progressive chemoreflex stress. In healthy free divers (n=7; 1 female; age range = 22 to 34 years) middle cerebral artery MFV (transcranial Doppler ultrasound; Multigon), mean arterial pressure (MAP; Finometer), central venous pressure (CVP; dependent antecubital vein), end tidal CO2 (ETCO2; ADInstruments), and hemoglobin saturation (HbSat, pulse oximetry) were measured while CPP (MAP‐CVP) and CVC (MFV/CPP) were calculated. These indices were obtained at baseline, during a 2‐min preparatory phase of rebreathing to establish early effects on CVC and CPP, and then during i) extended rebreathe (RB), ii) apnea at total lung capacity (TLC), or iii) apnea at functional residual capacity (FRC); each stress assigned randomly and continued to volitional tolerance. ETCO2 increased 12–18 mmHg in all conditions (Effect of Time, P<0.001; no Condition effect). The 59% HbSat level attained during RB was lower than FRC (78%) or TLC (80%) (Condition x Time interaction P<0.001). MFV was similar at baseline (TLC, 52±11; FRC, 49±8; RB, 51±11 cm/s) and increased similarly (Time effect, P<0.001) in TLC (111±17 cm/s), FRC (106±18 cm/s) and RB (108±11 cm/s; No Condition effect). CVC increased similarly in each condition (TLC, 49±11; FRC, 57±31; RB, 61±23%; Effect of Time P<0.001; No Condition effect). Also, CPP increased similarly in each condition (TLC, 46±16%; FRC, 42±14%; RB, 36±16%; Time effect P<0.001). The CVC response typically plateaued following the preparatory 2‐min rebreathe phase of each protocol whereas the majority of the CPP response occurred during the Apnea and extended rebreathe phases. Therefore, the determinants of the linear increase in MFV across the preparatory rebreathe phase, and the subsequent RB, TLC, or FRC condition phases, switched from a largely CVC mechanism at lower levels of stress, to increased CPP during the extended Apnea or RB manoeuvres, regardless of differences in HbSat.Support or Funding InformationNSERC discovery grant # 217916‐2013 awarded to J.K.S.