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Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Overlap Syndrome (OS), the co-occurrence of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease. Clustering of patients in subgroups with similar pre-clinical manifestations (ie, endothelial dysfunction) may identify relevant therapeutic phenotype categories for patients with OS who are at high risk of CVD. We therefore conducted a cross-sectional pilot study of endothelial function in 7 patients with OS (Forced Expiratory Volume in 1 second/Forced Vital Capacity < 0.7) on continuous positive airway pressure therapy (n = 7) to assess the relationship between FMD and physical activity. We found a strong association between FMD and step counts (rho = 0.77, p = 0.04); and FMD and moderate physical activity (rho = 0.9, p = 0.005). Further, larger studies are needed to confirm that FMD may identify patients with OS at high risk of CVD who benefit from increased physical activity.

Endothelial dysfunction (ED) plays a prominent role in the pathogenesis of preeclampsia (PE). There is a need for non-invasive methods to assess endothelial function in preeclamptic patients. In the present study, adropin, autotaxin (ATX), and lysophosphatidic acid (LPA) were evaluated as indicators of ED. Patients diagnosed with PE and healthy pregnant women (n = 42 for each group) were compared. After measuring flow-mediated dilation (FMD), the participants were stratified as ED (+) or ED (−) based on a cut-off value of 6.5%. The PE patients were divided as early/late onset PE and severe/mild PE. Adropin, ATX, and LPA levels were measured, and their relevance to ED was evaluated. Student t, Mann–Whitney U, or ANOVA tests were used for statistics, as appropriate. Adropin levels were diminished in the ED (+) group, whereas ATX and LPA levels were increased. The decrease in adropin levels was more pronounced in severe PE, showing a positive correlation with the FMD. In the logistic regression model, adropin was the only parameter that was an independent variable for the FMD test (P <.001). Adropin measurements in serum may be of value for disease follow-up in patients with PE. [ABSTRACT FROM AUTHOR]

Muscle hyperemia in exercise is usually the combined result of increased cardiac output and local muscle vasodilation, with the latter reflecting muscle's capacity for increased blood perfusion to support exercise. In this study, we aim to quantify muscle's vasodilation capability with dynamic BOLD imaging. A deoxyhemoglobin-kinetics model is proposed to analyze dynamic BOLD signals acquired during exercise recovery, deriving a hyperemia index (HI) for a muscle group of interest. We demonstrated the method's validity with calf muscles of healthy subjects who performed plantar flexion for muscle stimulation. In a test with exercise load incrementally increasing from 0 to 16 lbs., gastrocnemius HI showed considerable variance among the 4 subjects, but with a consistent trend, i.e. low at light load (e.g. 0–6 lbs) and linearly increasing at heavy load. The high variability among different subjects was confirmed with the other 10 subjects who exercised with a same moderate load of 8 lbs., with coefficient of variance among subjects' medial gastrocnemius 87.8%, lateral gastrocnemius 111.8% and soleus 132.3%. These findings align with the fact that intensive exercise induces high muscle hyperemia, but a comparison among different subjects is hard to make, presumably due to the subjects' different rate of oxygen utilization. For the same 10 subjects who exercised with load of 8 lbs., we also performed dynamic contrast enhanced (DCE) MRI to measure muscle perfusion (F). With a moderate correlation of 0.654, HI and F displayed three distinctive responses of calf muscles: soleus of all the subjects were in the cluster of low F and low HI, and gastrocnemius of most subjects had high F and either low or high HI. This finding suggests that parameter F encapsulates blood flow through vessels of all sizes, but BOLD-derived HI focuses on capillary flow and therefore is a more specific indicator of muscle vasodilation. In conclusion, the proposed hyperemia index has the potential of quantitatively assessing muscle vasodilation induced with exercise. [ABSTRACT FROM AUTHOR]

Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology. Hypoxia inhibits the activity of calcium channels in arterial myocytes by unknown mechanisms and contributes to arterial vasodilation. Here, the authors show that myocyte mitochondria are essential for sensing acute hypoxia and generate signals (NADH and H2O2) that modulate membrane calcium channels. [ABSTRACT FROM AUTHOR]

Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates. [ABSTRACT FROM AUTHOR]

Introduction: Single bouts of prolonged bent-legged sitting attenuate popliteal endothelial-dependent vasodilation (as assessed via flow-mediated dilation [FMD]), which is partially attributed to arterial 'kinking'. However, the impact of knee-flexion angle on sitting-induced popliteal FMD is unknown. The objective of this study was to perform separate laboratory and free-living studies to test the hypotheses that: (1) popliteal FMD impairments would be graded between knee flexions at 90° (bent-legged sitting) > 45° > 0° (straight-legged sitting) following a 3-hour bout of sitting; and (2) more habitual time spent bent-legged sitting (< 45°) would be associated with lower FMD. Methods: The laboratory study included eight young, healthy adults (24 ± 2 years; four women) who underwent two sitting bouts over 2 days with one leg positioned at a knee-flexion angle of 0° or 90° and the opposite leg at 45° knee flexion. Popliteal FMD was assessed at pre- and postsitting timepoints. Results: Sitting-induced reductions in FMD were similar between all knee-flexion angles (all, p > 0.674). The free-living study included 35 young, healthy adults (23 ± 3 years; 16 women) who wore three activPAL monitors (torso, thigh, shin) to determine detailed sedentary postures. Time spent sedentary (624 ± 127 min/day), straight-legged sitting (112 ± 98 min/day), and bent-legged sitting (442 ± 106 min/day) were not related to relative FMD (5.3 ± 1.8%; all, p > 0.240). Conclusion: These findings suggest that knee-flexion angle-mediated arterial 'kinking' during sitting is not a major contributor toward sitting-induced popliteal endothelial-dependent vasodilatory dysfunction. [ABSTRACT FROM AUTHOR]

Background and Purpose: Calcitonin gene‐related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP‐induced relaxation of human isolated coronary arteries (HCA). Experimental Approach: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration–response curves to human α‐CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation. Results: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL‐12330A, and PKA inhibitors Rp‐8‐Br‐cAMPs and H89, did not inhibit CGRP‐induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM‐34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM‐254890. Phosphodiesterase inhibitors induced a concentration‐dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries. Conclusion: While CGRP signalling is generally assumed to act via cAMP, the CGRP‐induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP‐induced relaxation than generally believed. [ABSTRACT FROM AUTHOR]

Purpose: Atherosclerotic disease of the forearm arteries can impede the maturation of distal fistulas in diabetic patients. The goal of this study was to look at the maturity of diabetic hemodialysis patients' distal forearm (radiocephalic snuffbox or distal forearm) arteriovenous fistulas. Materials and Methods: Patients with chronic renal failure who were candidates for distal forearm radiocephalic arteriovenous fistula implantation were evaluated in this cross-sectional study. Patients' demographic details, underlying disorders, laboratory measurements, vital signs, and information on their surgery were all noted. Patients were checked for fistula development 1 week, 1 month, 2 months, and then monthly until 6 months after surgery. Arteriovenous fistula maturation characterized by optimal blood flow, vessel dilation, and structural adaptations. Results: Among 343 patients (56% male, 44% female, mean age: 57.32 ± 12.48 years), hypertension prevailed (81.9%), followed by hyperlipidemia (42.3%) and coronary artery disease history (25.9%). AVFs achieved 58.3% maturation in 64.98 ± 11.05 days; higher BP during creation correlated with successful maturation (17.02 ± 1.46 mmHg vs 13.90 ± 1.93 mmHg, P <.05). No significant statistical difference found in distal forearm arteriovenous fistula maturation between males (57.8%) and females (58.9%) (P >.005). However, 41.7% of AVFs failed in 18.83 ± 17.89 days. Failed AVFs exhibited lower BP during operation and failure (11.75 ± 1.86 mmHg). Kaplan-Meier analysis depicted maturation probabilities over 90 days post-surgery. Conclusion: Diabetes and patient sex did not affect the maturation time of distal forearm AVFs in hemodialysis patients. Increased blood pressure during and after surgery correlated with shorter maturation time. [ABSTRACT FROM AUTHOR]

Background: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. Methods: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. Results: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. Conclusions: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether endothelin‐A receptor (ETAR) inhibition in non‐Hispanic Black (NHB) and White (NHW) young adults depends on biological sex. We recruited females during low hormone (n = 22) and high hormone (n = 22) phases, and males (n = 22). Participants self‐identified as NHB (n = 33) or NHW (n = 33). Participants were instrumented with two microdialysis fibers: (1) lactated Ringer's (control) and (2) 500 nM BQ‐123 (ETAR antagonist). Local heating was used to elicit cutaneous vasodilation, and an infusion of 20 mM L‐NAME to quantify NO‐dependent vasodilation. At control sites, NO‐dependent vasodilation was lowest in NHB males (46 ± 13 %NO) and NHB females during low hormone phases (47 ± 12 %NO) compared to all NHW groups. Inhibition of ETAR increased NO‐dependent vasodilation in NHB males (66 ± 13 %NO), in both groups of females during low hormone phases (NHW, control: 64 ± 12 %NO, BQ‐123: 85 ± 11 %NO; NHB, BQ‐123: 68 ± 13 %NO), and in NHB females during high hormone phases (control: 61 ± 11 %NO, BQ‐123: 83 ± 9 %NO). There was no effect for ETAR inhibition in NHW males or females during high hormone phases. These data suggest the effect of ETAR inhibition on NO‐dependent vasodilation is influenced by biological sex and racial identity. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pulmonary arterial hypertension (PAH), a rare fatal disorder characterised by inflammation, vascular remodelling and vasoconstriction. Current vasodilator therapies reduce pulmonary arterial pressure but not mortality. The G‐protein coupled formyl peptide receptors (FPRs) mediates vasodilatation and resolution of inflammation, actions possibly beneficial in PAH. We investigated dilator and anti‐inflammatory effects of the FPR biased agonist compound 17b in pulmonary vasculature using mouse precision‐cut lung slices (PCLS). Experimental Approach: PCLS from 8‐week‐old male and female C57BL/6 mice, intrapulmonary arteries were pre‐contracted with 5‐HT for concentration–response curves to compound 17b and 43, and standard‐of‐care drugs, sildenafil, iloprost and riociguat. Compound 17b‐mediated relaxation was assessed with FPR antagonists or inhibitors and in PCLS treated with TNF‐α or LPS. Cytokine release from TNF‐α‐ or LPS‐treated PCLS ± compound 17b was measured. Key Results: Compound 17b elicited concentration‐dependent vasodilation, with potencies of iloprost > compound 17b = riociguat > compound 43 = sildenafil. Compound 17b was inhibited by the FPR1 antagonist cyclosporin H but not by soluble guanylate cyclase, nitric oxide synthase or cyclooxygenase inhibitors. Under inflammatory conditions, the efficacy and potency of compound 17b were maintained, while iloprost and sildenafil were less effective. Additionally, compound 17b inhibited secretion of PAH‐relevant cytokines via FPR2. Conclusions and Implications: Vasodilation to compound 17b but not standard‐of‐care vasodilators, is maintained under inflammatory conditions, with additional inhibition of PAH‐relevant cytokine release. This provides the first evidence that targeting FPR, with biased agonist, simultaneously targets vascular function and inflammation, supporting the development of FPR‐based pharmacotherapy to treat PAH. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc [ABSTRACT FROM AUTHOR]

Background: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. Methods: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. Results: In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. Conclusions: Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization. [ABSTRACT FROM AUTHOR]

Considering the escalating global prevalence and the huge therapeutic demand for the treatment of hypertension, there is a persistent need to identify novel target sites for vasodilator action. This study aimed to investigate the role of TRPA1 channels in carvacrol-induced vasodilation and to design novel compounds based on carvacrol structure with improved activities. In an isolated tissue bath experiment, it was shown that 1 µM of the selective TRPA1 antagonist A967079 significantly (p < 0.001) reduced vasodilation induced by 3 mM of carvacrol. A reliable 3D-QSAR model with good statistical parameters was created (R2 = 0.83; Q2 = 0.59 and R p r e d 2 = 0.84) using 29 TRPA1 agonists. Obtained results from this model were used for the design of novel TRPA1 activators, and to predict their activity against TRPA1. Predicted pEC50 activities of these molecules range between 4.996 to 5.235 compared to experimental pEC50 of 4.77 for carvacrol. Molecular docking studies showed that designed molecules interact with similar amino acid residues of the TRPA1 channel as carvacrol, with eight compounds showing lower binding energies. In conclusion, carvacrol-induced vasodilation is partly mediated by the activation of TRPA1 channels. Combining different in silico approaches pointed out that the molecule D27 (2-[2-(hydroxymethyl)-4-methylphenyl]acetamide) is the best candidate for further synthesis and experimental evaluation in in vitro conditions. [ABSTRACT FROM AUTHOR]

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration. [ABSTRACT FROM AUTHOR]

Objective: The sympathetic–parasympathetic (or axo–axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on β2‐adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak β2‐adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine‐N‐methyltransferase (PNMT) and then acts on the β2‐adrenoceptors to induce neurogenic vasodilation. Methods: Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats. Results: Nicotine‐induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and Nω‐nitro‐l‐arginine. Nicotine‐ and exogenous NE‐induced vasorelaxation was partially inhibited by LY‐78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY‐78335; it then induced the release of nitric oxide (NO). Epinephrine‐induced vasorelaxation was not affected by LY‐78335. However, these vasorelaxations were completely inhibited by atenolol (a β1‐adrenoceptor antagonist) combined with ICI‐118,551 (a β2‐adrenoceptor antagonist). Conclusions: These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo–axonal interaction mechanism in regulating brainstem vascular tone. [ABSTRACT FROM AUTHOR]

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport. Integrating these systems together, model simulations reveal: (1.) To match expected flow and transmural flow ratios at increasing levels of exercise, a greater degree of vasodilation must occur in the subendocardium compared to the subepicardium. (2.) Oxygen extraction and venous oxygenation are predicted to substantially decrease with increasing exercise level preferentially in the subendocardium, suggesting that an oxygen-dependent error signal driving metabolic mediated recruitment of flow would be operative only in the subendocardium. (3.) Under baseline physiological conditions approximately 4% of the oxygen delivered to the subendocardium may be supplied via retrograde flow from coronary veins. [Display omitted] • The myocardium extracts >70% of the oxygen from inflowing arterial blood. • Myocardial contraction causes complex pulsatile transmural flow patterns. • We simulated transmural vasoregulation and oxygen delivery in the myocardium. • Simulations reveal insights into mechanisms governing metabolic mediated vasodilation [ABSTRACT FROM AUTHOR]

Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion. We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas. Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K+ channel inhibitors and prostaglandin D 2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels. Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K+ channels to dilate the nasal mucosal vasculature. [ABSTRACT FROM AUTHOR]

Background: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion. Methods: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas. Results: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K+ channel inhibitors and prostaglandin D2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels. Conclusions: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K+ channels to dilate the nasal mucosal vasculature.

The brain requires an uninterrupted supply of oxygen and nutrients to support the high metabolic needs of billions of nerve cells processing information. In low oxygen conditions, increases in cerebral blood flow maintain brain oxygen delivery, but the cellular and molecular mechanisms responsible for dilation of cerebral blood vessels in response to hypoxia are not fully understood. This article presents a systematic review and analysis of data reported in studies of these mechanisms. Our primary outcome measure was the percent reduction of the cerebrovascular response to hypoxia in conditions of pharmacological or genetic blockade of specific signaling mechanisms studied in experimental animals or in humans. Selection criteria were met by 28 articles describing the results of animal studies and six articles describing the results of studies conducted in humans. Selected studies investigated the potential involvement of various neurotransmitters, neuromodulators, vasoactive molecules and ion channels. Of all the experimental conditions, blockade of adenosine‐mediated signaling and inhibition of ATP‐sensitive potassium (KATP) channels had the most significant effect in reducing the cerebrovascular response to hypoxia (by 49% and 37%, respectively). Various degree reductions of the hypoxic response were also reported in studies which investigated the roles of nitric oxide, arachidonic acid derivates, catecholamines and hydrogen sulphide, amongst others. However, definitive conclusions about the importance of these signaling pathways cannot be drawn from the results of this analysis. In conclusion, there is significant evidence that one of the key mechanisms of hypoxic cerebral vasodilation (accounting for ∼50% of the response) involves the actions of adenosine and modulation of vascular KATP channels. However, recruitment of other vasodilatory signaling mechanisms is required for the full expression of the cerebrovascular response to hypoxia. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the regulatory effect of anserine on HUVEC cell injury and thrombosis in deep venous thrombosis (DVT) rats, and to elucidate the underlying molecular mechanisms. Methods: Non-targeted metabolomics data analyses were conducted using an ultra-performance liquid chromatography system Vanquish UHPLC and mass spectrometer to detect plasma metabolism profiles. The transcriptome sequencing and gene intervention experiments were performed to verify the regulatory effect. Further in vivo and in vitro experiments were performed. Enzyme-linked immunosorbent assay was used to detect the levels of P-selectin, E-selectin, and vWF, hematoxylin-eosin (HE) staining was performed to observe thrombotic and inflammatory cell infiltration, flow cytometry and TUNEL assays were performed to detect apoptosis, and qPCR and WB assays were conducted to determine the gene and protein expression. Results: Anserine alleviated HUVECs injury, reduced adhesion molecule expression, and inflammation. It decreased P-selectin, E-selectin, vWF, THBD, TFPI levels, and apoptosis while promoting NOS3, ET-1, and NO release in HUVECs. In DVT rats, anserine reduced P-selectin, E-selectin, vWF, thrombosis, cell infiltration, apoptosis, and promoted NO release. Transcriptome sequencing and gene intervention confirmed anserine's regulation of the PI3K-Akt pathway and coagulation via MYB. CARNMT1, a regulatory enzyme for anserine metabolism, increased anserine content, inhibiting coagulation, thrombosis, cell infiltration, and promoting NO release in rats. Conclusion: This study confirmed anserine could alleviate DVT by improving the inflammatory response, inhibiting blood agglutination, and promoting vasodilation, providing new potential therapeutic targets, important scientific evidence for the development of DVT management, and new clues for an indepth understanding of its molecular mechanisms. [ABSTRACT FROM AUTHOR]

Intra-abdominal organs are receptors that are more sensitive to temperature, cold. While the large vein area is effective because of the vasodilation process by giving warm compresses to reduce body temperature on the body surface. The purpose of this study was to determine the effectiveness of giving warm compresses to the abdominal wall (abdomen) and large vein (axilla) area to decrease the body temperature in fever patients. The design of this research is Quast-Experiment, Design with Nonequivalent Control Group Design approach. The population of this study was all patients with fever as many as 26 respondents. Samples were taken by consecutive sampling technique as many as 20 patients. The research variable is a warm compress in the axilla and abdomen and the independent variable is a decrease in body temperature. Data were collected by observing body temperature and analyzed by using the T-test. The results showed that abdominal compresses were more effective because the number of patients who did not experience a decrease was 1 respondent, while the axilla compression had 2 respondents. The results of the normality test of the data showed that the data were not normally distributed so that the hypothesis testing used the T-test and the results showed that the data was p = 0.000, = 0.05 so that p < a means Ho is rejected, meaning that the difference in body temperature decrease between giving axillary compresses and abdominal compresses is not too significant. and not that much different. [ABSTRACT FROM AUTHOR]

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small. [ABSTRACT FROM AUTHOR]

Horiuchi, Masahiro, Satomi Mitsui, and Tadashi Uno. Influence of smoking and alcohol habits on symptoms of acute mountain sickness on Mount Fuji: a questionnaire survey-based pilot study. High Alt Med Biol 00:000–000, 2024. Background: Acute cigarette smoking or alcohol intake would cause opposing vasculature effects that may influence acute mountain sickness (AMS). The present study aimed to investigate the effects of smoking and alcohol consumption behaviors, and acute smoking and consuming alcohol during ascent on AMS on Mount Fuji. Methods: This questionnaire survey study included 887 participants who climbed Mount Fuji and obtained information regarding sex, age, and smoking and alcohol habits, including behavior during ascent. Results: AMS prevalence was 45% for all participants. A univariate analysis revealed that younger participants (20–29 years) were associated with increased AMS prevalence (effect size [ES] = 0.102, p = 0.057) and severity (ES = 0.18, p = 0.01). A prediction model using multiple logistic regression indicated that several factors influenced AMS risk: younger age (p = 0.001), daily smoking habits (p = 0.021), no smoking (p = 0.033), or alcohol consumption during ascent (p = 0.096). Alcohol consumption during ascent had no effect on the increased AMS risk in younger participants (20–29 years), while alcohol consumption during ascent increased AMS risk for middle-age participants (50–59 years). Conclusion: Younger individuals are more likely to experience AMS. Smoking habits are associated with an increased AMS risk. It may be recommended that middle-aged climbers should ascend without consuming alcohol. [ABSTRACT FROM AUTHOR]

Vasculogenic erectile dysfunction (ED) is the most common form of ED affecting the male population. Once the first line investigation for erectile dysfunction, penile Doppler ultrasound examinations have reduced in number following the introduction of oral phosphodiesterase inhibitors as a treatment method. As such, skilled professionals versed in the performance of these examinations are dwindling. This skill deficit is compounded by the lack of standardisation that exists in the performance and interpretation of penile haemodynamics relative to impotence of vascular origin. Despite the success of pharmacological agents in the treatment of vasculogenic dysfunction, penile Doppler examinations are still relevant in the assessment of ED in non‐responders, and those patients in which pelvic surgery or trauma has altered the normal erectile mechanism. Growing evidence in the literature also suggests that vasculogenic ED may be an early indicator of systemic vascular disease and therefore prognostic of future cardiovascular events. Considering this, the relevance of Doppler assessment of penile haemodynamics with ultrasound should not be underestimated. This article will introduce the sonographer to advanced vascular anatomy of the penis, pathophysiology of erectile function and the principles of normal and pathological penile haemodynamic patterns. It also aims to suggest a standardised protocol for the performance of penile Doppler ultrasound relative to primary vasculogenic ED and reduce the amount of variability that exits between operators. As such the sonographer can make a significant contribution to patient management pathways. [ABSTRACT FROM AUTHOR]

Red light (670 nm) energy controls vasodilation via the formation of a transferable endothelium-derived nitric oxide (NO)-precursor-containing substance, its intracellular traffic, and exocytosis. Here we investigated the underlying mechanistic effect of oxidative stress on light-mediated vasodilation by using pressure myography on dissected murine arteries and immunofluorescence on endothelial cells. Treatment with antioxidants Trolox and catalase decreased vessel dilation. In the presence of catalase, a lower number of exosomes were detected in the vessel bath. Light exposure resulted in increased cellular free radical levels. Mitochondrial reactive oxygen species were also more abundant but did not alter cellular ATP production. Red light enhanced the co-localization of late exosome marker CD63 and cellular S-nitrosoprotein to a greater extent than high glucose, suggesting that a mild oxidative stress favors the localization of NO precursor in late exosomes. Exocytosis regulating protein Rab11 was more abundant after irradiation. Our findings conclude that red-light-induced gentle oxidative stress facilitates the dilation of blood vessels, most likely through empowering the traffic of vasodilatory substances. Application of antioxidants disfavors this mechanism. [ABSTRACT FROM AUTHOR]

Mitochondrial ATP-sensitive K+ (mitoK ATP) channels are involved in neuronal and cardiac protection from ischemia and oxidative stress. Penile erection is a neurovascular event mediated by relaxation of the erectile tissue via nitric oxide (NO) released from nerves and endothelium. In the present study, we investigated whether mitoK ATP channels play a role in the control of penile vascular tone and mitochondrial dynamics, and the involvement of NO. The effect of the selective mitoK ATP activator BMS191095 was examined on vascular tone, on mitochondrial bioenergetics by real-time measurements with Agilent Seahorse and on ROS production by MitoSOX fluorescence in freshly isolated microarteries. BMS191095 and diazoxide relaxed penile arteries, BMS191095 being one order of magnitude more potent. BMS191095-induced relaxations were reduced by mechanical endothelium removal and by inhibitors of the nitric oxide synthase (NOS) and PI3K enzymes. The NO-dependent component of the relaxation to BMS191095 was impaired in penile arteries from insulin resistant obese rats. The blockers of mitoK ATP channel 5-HD, sarcolemma K ATP (sarcK ATP) channel glibenclamide, and large conductance Ca2+-activated K+ (BK Ca) channel iberiotoxin, inhibited relaxations to BMS191095 and to the NO donor SNAP. BMS191095 reduced the mitochondrial bioenergetic profile of penile arteries and attenuated mitochondrial ROS production. Blockade of endogenous NO impaired and exogenous NO mimicked, respectively, the inhibitory effects of BMS191095 on basal respiration and oxygen consumed for ATP synthesis. Exogenous NO exhibited dual inhibitory/stimulatory effects on mitochondrial respiration. These results demonstrate that selective activation of mitoK ATP channels causes penile vasodilation, attenuates ROS production and inhibits mitochondrial respiration in part by releasing endothelial NO. These mechanisms couple blood flow and metabolism in penile arterial wall and suggest that activation of vascular mitoK ATP channels may protect erectile tissue against ischemic injury. [Display omitted] • mitoK ATP channel activation releases NO from endothelium that further activates adjacent VSM mitoK ATP and BK Ca channels to induce penile vasodilation. • Relaxations induced by mitoK ATP channel activation are impaired in penile arteries from insulin resistant obese rats. • mitoK ATP channel activation inhibits ROS generation and attenuates mitochondrial respiration in penile VSM in part through the release of endothelial NO. • mitoK ATP channel openers couple blood flow and metabolism in penile arterial wall and might protect erectile tissue against ischemic injury. [ABSTRACT FROM AUTHOR]

Hormone-sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet-induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high-fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild-type mice. CBF was positively correlated with lectin-stained vessel density. HSL deletion did not exacerbate HFD-induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild-type mice, and HSL deletion did not significantly aggravate HFD-induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD-induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet-induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD-induced neuroinflammation and memory dysfunction. [ABSTRACT FROM AUTHOR]

Spreading depolarization (SD) is an electrochemical wave of neuronal depolarization mediated by extracellular K+ and glutamate, interacting with voltage-gated and ligandgated ion channels. SD is increasingly recognized as a major cause of injury progression in stroke and brain trauma, where the mechanisms of SD-induced neuronal injury are intimately linked to energetic status and metabolic impairment. Here, I review the established working model of SD initiation and propagation. Then, I summarize the historical and recent evidence for the metabolic impact of SD, transitioning from a descriptive to a mechanistic working model of metabolic signaling and its potential to promote neuronal survival and resilience. I quantify the energetic cost of restoring ionic gradients eroded during SD, and the extent to which ion pumping impacts high-energy phosphate pools and the energy charge of affected tissue. I link energy deficits to adaptive increases in the utilization of glucose and O2, and the resulting accumulation of lactic acid and CO2 downstream of catabolic metabolic activity. Finally, I discuss the neuromodulatory and vasoactive paracrine signaling mediated by adenosine and acidosis, highlighting these metabolites' potential to protect vulnerable tissue in the context of high-frequency SD clusters. [ABSTRACT FROM AUTHOR]

The mechanisms behind renal vasodilatation elicited by stimulation of β‐adrenergic receptors are not clarified. As several classes of K channels are potentially activated, we tested the hypothesis that KV7 and BKCa channels contribute to the decreased renal vascular tone in vivo and in vitro. Changes in renal blood flow (RBF) during β‐adrenergic stimulation were measured in anaesthetized rats using an ultrasonic flow probe. The isometric tension of segmental arteries from normo‐ and hypertensive rats and segmental arteries from wild‐type mice and mice lacking functional KV7.1 channels was examined in a wire‐myograph. The β‐adrenergic agonist isoprenaline increased RBF significantly in vivo. Neither activation nor inhibition of KV7 and BKCa channels affected the β‐adrenergic RBF response. In segmental arteries from normo‐ and hypertensive rats, inhibition of KV7 channels significantly decreased the β‐adrenergic vasorelaxation. However, inhibiting BKCa channels was equally effective in reducing the β‐adrenergic vasorelaxation. The β‐adrenergic vasorelaxation was not different between segmental arteries from wild‐type mice and mice lacking KV7.1 channels. As opposed to rats, inhibition of KV7 channels did not affect the murine β‐adrenergic vasorelaxation. Although inhibition and activation of KV7 channels or BKCa channels significantly changed baseline RBF in vivo, none of the treatments affected β‐adrenergic vasodilatation. In isolated segmental arteries, however, inhibition of KV7 and BKCa channels significantly reduced the β‐adrenergic vasorelaxation, indicating that the regulation of RBF in vivo is driven by several actors in order to maintain an adequate RBF. Our data illustrates the challenge in extrapolating results from in vitro to in vivo conditions. What is the central question of this study?Does activation of KV7 or BKCa channels drive renal β‐adrenergic vasodilatation?What is the main finding and its importance?KV7 and BKCa channels contribute significantly to renal β‐adrenergic vasorelaxation in vitro but have no effect in vivo although inhibition of KV7 and BKCa channels significantly reduce baseline renal blood flow. These findings highlight the importance of in vivo studies where several different mechanisms may compensate each other. [ABSTRACT FROM AUTHOR]

INTRODUCTION Despite electronic cigarettes (e-cigarettes) being marketed as a safer alternative to combustible cigarettes, the effects of chronic e-cigarette use on vascular health remain uncertain. Our meta-analysis aimed to assess the health implications of chronic exclusive e-cigarette use on endothelial dysfunction, as measured by flow-mediated vasodilation (FMD). METHODS PubMed, Embase and Scopus were searched for studies from 1 January 2004 to 31 March 2024. Four cross-sectional studies (n=769) were pooled using a random-effects model. The mean differences (MD) of FMD were reported by comparing exclusive e-cigarette use versus non-use; exclusive e-cigarette use versus combustible cigarette use; and combustible cigarette use versus non-use. RESULTS A non-significant reduction in FMD in exclusive e-cigarette use compared to non-use was reported (MD of FMD: -1.47%; 95% CI: -3.96 - 1.02; I²= 84%). Similar MD of FMD in exclusive e-cigarette use and exclusive combustible cigarette use (vs non-use) suggested that both of these products might have comparable adverse influences on endothelial health. CONCLUSIONS The limited availability of studies assessing the chronic impact of e-cigarette use restricted our ability to provide definitive findings. We emphasize the importance of additional research that explores the long-term impact of e-cigarette use on endothelial dysfunction, and identify key areas and give suggestions for further study. [ABSTRACT FROM AUTHOR]

Purpose: Cold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI). Methods: Eleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured. Results: Flavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05). Conclusion: These data suggest that cocoa flavanol ingestion does not alter finger CIVD. Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020. [ABSTRACT FROM AUTHOR]

Migraine is one of the world's most debilitating disorders, and it has recently been shown that changes in the retina can be a potential biomarker for the disease. These changes can be detected by optical coherence tomography (OCT), which measures retinal thickness, and optical coherence tomography angiography (OCTA), which measures vessel density. We searched the databases Google Scholar, ProQuest, Scopus, and Web of Science for studies in English using OCT and OCTA in migraineurs, using the search terms "optical coherence tomography," "OCT," "optical coherence tomography angiography," "OCTA" and "migraine." We found 73 primary studies, 11 reviews, and 8 metaanalyses pertaining to OCT and OCTA findings in migraineurs. They showed that migraineurs had reduced retinal thickness (via OCT), retinal vessel density, and greater foveal avascular zone area (via OCTA) than controls. OCTA changes reflect a perfusion compromise occurring in migraineurs as opposed to in healthy controls. OCT and OCTA deficits were worse in migraine-with-aura and chronic migraine than in migraine-without-aura and episodic migraine. Certain areas of the eye, such as the fovea, may be more vulnerable to these perfusion changes than other parts. Direct comparison between study findings is difficult because of the heterogeneity between the studies in terms of both methodology and analysis. Moreover, as almost all case-control studies were cross-sectional, more longitudinal cohort studies are needed to determine cause and effect between migraine pathophysiology and OCT/OCTA findings. Current evidence suggests both OCT and OCTA may serve as retinal markers for migraineurs, and further research in this field will hopefully enable us to better understand the vascular changes associated with migraine, perhaps also providing a new diagnostic and therapeutic biomarker. [ABSTRACT FROM AUTHOR]

Glycophorin A and glycophorin B are structural membrane glycoproteins bound in the band 3 multiprotein complexes on human red blood cells (RBCs). Band 3 is an erythroid-specific anion exchanger (AE1). AE1-mediated HCO3− transport provides the substrate for the enzyme-catalyzed conversion HCO3− (aq) # CO2(g), which takes place inside the RBCs. Bicarbonate transport via AE1 supports intravascular acid–base homeostasis and respiratory excretion of CO2. In the past decade, we conducted several comparative physiology studies on Taiwanese people having the glycophorin variant GPMur RBC type (which accompanies greater AE1 expression). We found that increased anion transport across the erythrocyte membrane not only enhances gas exchange and lung functions but also elevates blood pressure (BP) and reduces nitric oxide (NO)- dependent vasodilation and exhaled NO fraction (FeNO) in healthy individuals with GP.Mur. Notably, in people carrying the GPMur blood type, the BP and NO-dependent, flow-mediated vasodilation (FMD) are both more strongly correlated with individual hemoglobin (Hb) levels. As blood NO and nitrite (NO2− ) are predominantly scavenged by intraerythrocytic Hb, and NO2− primarily enters RBCs via AE1, could a more monoanion-permeable RBC membrane (i.e., GPMur/ increased AE1) enhance NO2− /NO3− permeability and Hb scavenging of NO2− and NO to affect blood pressure? In this perspective, a working model is proposed for the potential role of AE1 in intravascular NO availability, blood pressure, and clinical relevance. [ABSTRACT FROM AUTHOR]

We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non‐Hispanic Black and non‐Hispanic White participants (n = 15 per group). Participants were instrumented with four microdialysis fibers: (1) lactated Ringer's (control), (2) 10 μM tempol (superoxide inhibition), (3) 0.1 mM 1400 W (iNOS inhibition), (4) tempol + 1400 W. Cutaneous vasodilation was induced via local heating and NO‐dependent vasodilation was quantified. At control sites, NO‐dependent vasodilation was lower in non‐Hispanic Black (45 ± 9% NO) relative to non‐Hispanic White (79 ± 9% NO; p < 0.01; effect size, d = 3.78) participants. Tempol (62 ± 16% NO), 1400 W (78 ± 12% NO) and tempol +1400 W (80 ± 13% NO) increased NO‐dependent vasodilation in non‐Hispanic Black participants relative to control sites (all p < 0.01; d = 1.22, 3.05, 3.03, respectively). The effect of 1400 W (p = 0.04, d = 1.11) and tempol +1400 W (p = 0.03, d = 1.22) was greater than tempol in non‐Hispanic Black participants. There was no difference between non‐Hispanic Black and non‐Hispanic White participants at 1400 W or tempol + 1400 W sites. These data suggest iNOS has a greater effect on NO‐dependent vasodilation than superoxide in non‐Hispanic Black participants. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) line the wall of blood vessels and regulate arterial contractility to tune regional organ blood flow and systemic pressure. Chloride (Cl-) is the most abundant anion in ECs and the Cl- sensitive With-No-Lysine (WNK) kinase is expressed in this cell type. Whether intracellular Cl- signaling and WNK kinase regulate EC function to alter arterial contractility is unclear. Here, we tested the hypothesis that intracellular Cl- signaling in ECs regulates arterial contractility and examined the signaling mechanisms involved, including the participation of WNK kinase. Our data obtained using two-photon microscopy and cell-specific inducible knockout mice indicated that acetylcholine, a prototypical vasodilator, stimulated a rapid reduction in intracellular Cl- concentration ([Cl-]i) due to the activation of TMEM16A, a Cl- channel, in ECs of resistance-size arteries. TMEM16A channel-mediated Cl- signaling activated WNK kinase, which phosphorylated its substrate proteins SPAK and OSR1 in ECs. OSR1 potentiated transient receptor potential vanilloid 4 (TRPV4) currents in a kinase-dependent manner and required a conserved binding motif located in the channel C terminus. Intracellular Ca2+ signaling was measured in four dimensions in ECs using a high-speed lightsheet microscope. WNK kinase-dependent activation of TRPV4 channels increased local intracellular Ca2+ signaling in ECs and produced vasodilation. In summary, we show that TMEM16A channel activation reduces [Cl-]i, which activates WNK kinase in ECs. WNK kinase phosphorylates OSR1 which then stimulates TRPV4 channels to produce vasodilation. Thus, TMEM16A channels regulate intracellular Cl- signaling and WNK kinase activity in ECs to control arterial contractility. [ABSTRACT FROM AUTHOR]

Introduction: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) improves end-organ perfusion in cardiogenic shock but may increase afterload, which can limit cardiac recovery. Left ventricular (LV) unloading strategies may aid cardiac recovery and prevent complications of increased afterload. However, there is no consensus on when and which unloading strategy should be used. Methods: An online survey was distributed worldwide via the EuroELSO newsletter mailing list to describe contemporary international practice and evaluate heterogeneity in strategies for LV unloading. Results: Of 192 respondents from 43 countries, 53% routinely use mechanical LV unloading, to promote ventricular recovery and/or to prevent complications. Of those that do not routinely unload, 65% cited risk of complications as the reason. The most common indications for unplanned unloading were reduced arterial line pulsatility (68%), pulmonary edema (64%) and LV dilatation (50%). An intra-aortic balloon pump was the most frequently used device for unloading followed by percutaneous left ventricular assist devices. Echocardiography was the most frequently used method to monitor the response to unloading. Conclusions: Significant variation exists with respect to international practice of ventricular unloading. Further research is required that compares the efficacy of different unloading strategies and a randomized comparison of routine mechanical unloading versus unplanned unloading. [ABSTRACT FROM AUTHOR]