Differences In Vascular Reactivity Research Articles

Cerebrovascular reactivity increases across development in multiple networks as revealed by a breath-holding task: A longitudinal fMRI study.

Functional magnetic resonance imaging (fMRI) has been widely used to understand the neurodevelopmental changes that occur in cognition and behavior across childhood. The blood-oxygen-level-dependent (BOLD) signal obtained from fMRI is understood to be comprised of both neuronal and vascular information. However, it is unclear whether the vascular response is altered across age in studies investigating development in children. Since the breath-hold (BH) task is commonly used to understand cerebrovascular reactivity (CVR) in fMRI studies, it can be used to account for developmental differences in vascular response. This study examines how the cerebrovascular response changes over age in a longitudinal children's BH data set from the Nathan Kline Institute (NKI) Rockland Sample (aged 6-18 years old at enrollment). A general linear model approach was applied to derive CVR from BH data. To model both the longitudinal and cross-sectional effects of age on BH response, we used mixed-effects modeling with the following terms: linear, quadratic, logarithmic, and quadratic-logarithmic, to find the best-fitting model. We observed increased BH BOLD signals in multiple networks across age, in which linear and logarithmic mixed-effects models provided the best fit with the lowest Akaike information criterion scores. This shows that the cerebrovascular response increases across development in a brain network-specific manner. Therefore, fMRI studies investigating the developmental period should account for cerebrovascular changes that occur with age.

The pig is a better model than the rabbit or rat for studying the pathophysiology of human mesenteric arteries.

Animal models are essential to investigate cardiovascular pathophysiology and pharmacology, but phylogenetic diversity makes it necessary to identify the model with vasculature most similar to that of humans. In this study, we compared the mesenteric arteries of humans, pigs, rabbits and rats in terms of the i) evolutionary changes in the amino acid sequences of α1 and β2 adrenoceptors; M1, M2, and M3 muscarinic receptors; and bradykinin (BKR) and thromboxane-prostanoid (TP) receptors, through bioinformatics tools; ii) expression of α1, β2, M1, M3 and TP receptors in each tunica, as assessed by immunofluorescence; and iii) reactivity to receptor-dependent and independent contractile agonists and relaxants, by performing organ bath assays. Phylogenetically, pigs showed the highest degree of evolutionary closeness to humans for all receptors, and with the exception of BKR, rabbits presented the greatest evolutionary difference compared to humans, pigs and rats. The expression of the measured receptors in the three vascular tunica in pigs was most similar to that in humans. Using a one-way ANOVA to determine the differences in vascular reactivity, we found that the reactivity of pigs was the most similar to that of humans in terms of sensitivity (pD2) and maximum effect of vascular reactivity (Emax) to KCl, phenylephrine, isoproterenol and carbachol. The pig is a better vascular model than the rabbit or rat to extrapolate results to human mesenteric arteries. Comparative vascular studies have implications for understanding the evolutionary history of different species. The presented findings are useful for identifying an animal model with a vasculature that is similar to that of humans. This information is important to extrapolate, with greater precision, the findings in arterial pathophysiology or pharmacology from animal models to the healthy or diseased human being.

Sex Differences in Vascular Response to Mental Stress and Adverse Cardiovascular Events Among Patients With Ischemic Heart Disease.

Microvascular measures of vascular dysfunction during acute mental stress may be important determinants of major adverse cardiovascular events (MACE), especially among younger and middle-aged women survivors of an acute myocardial infarction. In the MIMS2 study (Myocardial Infarction and Mental Stress 2), individuals who had been hospitalized for a myocardial infarction in the past 8 months were prospectively followed for 5 years. MACE was defined as a composite index of cardiovascular death and first/recurring events for nonfatal myocardial infarction and hospitalizations for heart failure. Reactive hyperemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task. Survival models for recurrent events were used to examine the association between vascular response to stress (difference between poststress and resting values) and MACE. Reactive hyperemia index and flow-mediated dilation were standardized in analyses. Of 263 patients (the mean age was 51 years; range, 25-61), 48% were women, and 65% were Black. During a median follow-up of 4.3 years, 64 patients had 141 adverse cardiovascular events (first and repeated). Worse microvascular response to stress (for each SD decrease in the reactive hyperemia index) was associated with 50% greater risk of MACE (hazard ratio, 1.50 [95% CI, 1.05-2.13]; P=0.03) among women only (sex interaction: P=0.03). Worse transient endothelial dysfunction in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (hazard ratio, 1.35 [95% CI, 1.07-1.71]; P=0.01), and the association was similar in women and men. Peripheral microvascular dysfunction with mental stress was associated with adverse events among women but not men. In contrast, endothelial dysfunction was similarly related to MACE among both men and women. These results suggest a female-specific mechanism linking psychological stress to adverse outcomes.

Differences in vascular reactivity to soluble guanylate cyclase agonists between female and castrated male pigs

This study investigated whether there are sex differences in vasorelaxation through the nitric oxide (NO)/soluble guanylate cyclase (sGC) pathway. The hearts of female (F) and castrated male (CM) pigs (6-month-old) were collected at a local abattoir, and left anterior descending coronary arteries were isolated to perform organ chamber experiments. Vasorelaxant activity was assessed based on the pD2 values. Bradykinin induced a concentration-dependent relaxation, which was comparable between F [8.55±0.13] and CM [8.67±0.11]. In the presence of L-NAME (100 μM, NO synthase inhibitor), the response to bradykinin was attenuated similarly in F [7.27±0.24] and CM [7.42±0.29]. Sodium nitroprusside (SNP, reduced sGC agonist) also induced relaxation in a concentration-dependent manner, and the potency in F [6.54±0.12] was similar to that in CM [6.50±0.11]. Pretreatment with ODQ (10 μM, sGC heme oxidant) attenuated SNP-induced relaxation similarly in F [4.77±0.19] and CM [4.78±0.09]. Likewise, there were no differences in BAY 60-2770 (oxidized/apo sGC agonist)-induced relaxation irrespective of the presence [10.64±0.20 (F) vs. 10.47±0.14 (CM)] or absence [9.89±0.11 (F) vs. 9.67±0.15 (CM)] of ODQ. These findings suggest that there are no differences in the regulation of coronary artery tone in response to sGC agonists between F and CM.

Similar inflammatory response and conduit artery vascular function between sexes following induced inflammation

What is the central question of this study? Are there sex differences in vascular function following induced inflammation when oestrogen is typically similar between sexes? What is the main finding and its importance? The present study suggests no sex differences in conduit artery vascular responses to acutely induced inflammation during the low-oestrogen phase of the menstrual cycle in premenopausal women. However, women exhibit lower microvascular function than men. Overall, the results underpin the role of oestrogen in previously observed sex differences and the importance of reporting the phase in the hormonal cycle when women are studied. Sex differences in cardiovascular disease incidence in premenopausal women and age-matched men have been attributed to the cardioprotective influence of oestrogen. However, limited knowledge exists regarding sex differences following acute inflammation when oestrogen concentrations are lower in women. We evaluated sex differences in vascular responses to induced inflammation when oestrogen concentrations are typically lower in women (early follicular phase or placebo phase of hormonal contraception). In 15 women and 14 men, interleukin-6 (IL-6) concentrations and vascular function [via brachial artery flow-mediated dilatation (FMD)] were assessed at baseline (BL) and 24 (24H) and 48hours (48H) after administration of influenza vaccine. After induction of inflammation, both sexes exhibited an increase in IL-6 concentrations at 24H [mean (SD) BL vs. 24H: women, 0.563 (0.50) vs. 1.141 (0.65) pg/ml; men, 0.385 (0.17) vs. 1.113 (0.69) pg/ml; P<0.05] that returned to near-baseline concentrations by 48H (BL vs. 48H, P>0.05). There were no sex differences in FMD, allometrically scaled FMD or IL-6 concentrations at any time point (P>0.05). Notably, women exhibited significantly lower microvascular function than men at every time point [P<0.05; reactive hyperaemic area under the curve (in arbitrary units): women, BL 35,512 (14,916), 24H 34,428 (14,292) and 48H 39,467 (13,936); men, BL 61,748 (27,324), 24H 75,028 (29,051) and 48H 59,532 (13,960)]. When oestrogen concentrations are typically lower in women, women exhibit a similar inflammatory response and conduit artery function, but lower microvascular response to reactive hyperaemia, in comparison to age-matched men.

Fitness Level- and Sex-Related Differences in Macrovascular and Microvascular Responses during Reactive Hyperemia.

Reactive hyperemia (RH) is widely used for the investigation of macrovascular (flow-mediated dilation, or FMD) and microvascular (near-infrared spectroscopy-vascular occlusion test, or NIRS-VOT) function. Mixed results have been reported on fitness level- and sex-related differences in FMD outcomes, and little is known about microvascular differences in untrained and chronically trained males and females. Fifteen chronically trained (CT: 8 males, 7 females) and 16 untrained (UT: 8 males, 8 females) individuals participated in this study. Aerobic fitness (V˙O2max) was assessed during a cycling incremental exercise test to volitional exhaustion. FMD and NIRS-VOT were performed simultaneously on the lower limb investigating superficial femoral artery and vastus lateralis muscle, respectively. %FMD was not different between groups (CT males, 4.62 ± 1.42; CT females, 4.15 ± 2.23; UT males, 5.10 ± 2.53; CT females, 3.20 ± 1.67). Peak blood flow showed greater values in CT versus UT (P ≤ 0.0001) and males versus females (P = 0.032). RH blood flow area under the curve was greater in CT versus UT (P = 0.001). At the microvascular level, desaturation and reperfusion rates were faster in CT versus UT (P = 0.018 and P = 0.013) and males versus females (P = 0.011 and P = 0.005). V˙O2max was significantly correlated with reperfusion rate (P = 0.0005) but not with %FMD. Whereas NIRS-VOT outcomes identified fitness- and sex-related differences in vascular responses, %FMD did not. However, when RH-related outcomes from the FMD analysis were considered, fitness- and/or sex-related differences were detected. These data highlight the importance of integrating FMD and NIRS-VOT outcomes for a more comprehensive evaluation of vascular function.

No Sex Differences in Inflammatory Response and Vascular Function During Low Estrogen Phase

Premenopausal women experience a lower incidence of cardiovascular disease as compared to age-matched men, partially due to the cardioprotective effects of estrogen. Acute inflammation increases pro-inflammatory cytokine production and reduces nitric oxide bioavailability, resulting in impaired vascular function. Estrogen has both anti-inflammatory and pro-vasodilatory properties. During the high estrogen mid-luteal phase of the menstrual cycle, sex differences in vascular function and inflammatory responses to induced inflammation have been observed in premenopausal women as compared with age-matched men. However, limited knowledge exists regarding sex differences in estrogen independent responses to acute inflammation. Thus, our objective was to evaluate sex differences in vascular responses to induced inflammation- with a reduced influence of estrogen concentration. Due to the dampening of estrogen-related anti-inflammatory and pro-vasodilatory effects when estrogen concentrations are low, we hypothesized that women would experience a greater inflammatory response as compared with men and that women and men would exhibit similar vascular function. In a double-blind crossover sham-controlled study of 15 women (21 ± 3y) and 15 men (21 ± 2y), we assessed pro-inflammatory interleukin-6 concentration ([IL-6]) and vascular function via brachial artery flow-mediated dilation (FMD) at baseline (BL), 24 hours (24H), and 48 hours (48H) after influenza vaccine administration. Women were studied when circulating estrogen levels are typically low (early follicular phase or placebo pill phase of oral contraceptive pills) and similar between sexes. Following induced inflammation, both sexes exhibited an increase in [IL-6] at 24H (BL v 24H: women p=0.0049; men p=0.0015) that returned to near baseline levels by 48H (BL v 48H: women p=0.43; men p=0.29; [IL-6] (pg/mL): women BL: 0.56 ± 0.5, 24H: 1.14 ± 0.7, 48H: 0.59 ± 0.4; men BL: 0.38 ± 0.2, 24H: 1.05 ± 0.7, 48H: 0.56 ± 0.2). There were no sex differences in FMD or [IL-6] at any time point (FMD: sex p=0.062, time p=0.30, interaction p=0.25; FMD (%): women BL: 8.33 ± 4.8, 24H: 6.40 ± 4.4, 48H: 9.05 ± 5.5; men: BL: 5.25 ± 2.9, 24H: 6.14 ± 2.1, 48H: 6.71 ± 1.1; [IL-6]: BL: p=0.38, 24H: p=0.57, 48H: p=0.99). Notably, women exhibited significantly lower resting brachial artery diameter (BL D; p<0.0001 all time points) than men (BL D (mm): women BL: 3.22 ± 0.4, 24H: 3.18 ± 0.4, 48H: 3.19 ± 0.4; men BL: 4.07 ± 0.6, 24H: 4.24 ± 0.4, 48H, 4.22 ± 0.4). Due to sex difference in baseline diameter, we allometrically scaled FMD to normalize the flow-mediated response to variability in baseline diameter between the sexes. However, there were no sex differences in allometrically scaled FMD (sex p=0.11, time p=0.20, interaction p= 0.072; Scaled FMD (%): women BL: 6.39 ± 3.7, 24H: 4.32 ± 3.8, 48H: 6.92 ± 3.7; men BL: 7.03 ± 3.9, 24H: 8.71 ± 4.2, 48H: 8.69 ± 4.3). When estrogen concentrations are low, women show similar inflammatory responses and vascular function as compared with age-matched men, suggesting a primary role of estrogen in previously observed sex differences in inflammatory responses and vascular function.

Sex Differences in Vascular Reactivity with Acute and Chronic Hypoxia

Objective Males and females may respond differently to hypoxic exposure at high altitude. Females have reduced vascular resistance in response to hypoxia, possibly due to differences in adrenergic control. We investigated the role of sex in vascular control during hypoxia. We hypothesized females have reduced vasoreactivity to sympathetic stressors compared to males during acute and prolonged hypoxia exposure. Methods We studied a convenient sample of 7 males and 6 females at three time points: 1) low altitude (Calgary AB, 1100m) breathing room air (normoxia; LOW) and acute isocapnic hypoxia (PETO2~50mmHg; PETCO2~32mmHg; ACUTE); 2) during early (day 2-3; EARLY) and 3) late (day 8-10; LATE) acclimatization at high altitude (White Mountain, CA; 3800m) breathing room air (PETO2~50mmHg) and hyperoxia (100% O2). Heart rate (HR), mean arterial pressure (MAP), and blood oxygen saturation (SpO2) were collected beat-by-beat. Participants performed a cold pressor test (CPT) to assess integrated cardiovascular reactivity to a sympathetic stressor. To isolate α1-adrenergic receptor sensitivity, we delivered a graded series of phenylephrine hydrochloride (PE) injections. Statistical analysis included a mixed model ANOVA, and Holm-Sidak post hoc tests when we identified main effects (α<0.05). Results In response to CPT, peak change in MAP decreased with hypoxia duration (p<0.001). There was also a significant interaction between condition and sex (p=0.038). While LOW (+17.0±5.9mmHg) and ACUTE (+15.3±4.7mmHg) responses were not different (p=0.565), males showed a marked decrease in peak MAP response to CPT at EARLY (+10.2±4.9mmHg) and LATE (+9.8±5.4mmHg) compared to LOW (both p<0.001). Similarly, LOW (+11.8±8.4mmHg) and ACUTE (+8.2±3.8mmHg) peak MAP responses to CPT were not different in females (p=0.137). Though female responses decreased between LOW and EARLY (+6.3±3.3mmHg; p=0.042), they returned to similar values by LATE (+9.7±7.5mmHg; p=0.479). Adrenergic sensitivity slope was decreased at altitude (p=0.025) independent of sex (p=0.977). LOW (0.33±0.21) and ACUTE (0.22±0.10) sensitivity were not different (p=0.309). Notably, sensitivity was reduced at altitude at LATE (0.14±0.16; p=0.043), but not significantly at EARLY (0.16±0.18; p=0.051) compared to LOW. Hyperoxia did not correct CPT responses or PE adrenergic sensitivity to low altitude values at EARLY (p<0.001; p=0.01, respectively) nor LATE (p=0.013; p=0.042, respectively). Conclusions Our data indicate decreased α1-adrenergic responsiveness with acclimatization underlies blunted vascular reactivity in both sexes. However, female responses to CPT returned to low altitude values following 8 days at altitude, indicating differential adaptation. Additional mechanisms influencing the vascular response to stress (e.g. less neuropeptide mediated constriction, higher β-adrenergic dilation) may account for lower responsiveness in females compared to males. Our results have implications for understanding vascular function at high altitude and in clinical conditions characterized by hypoxemia.

Impaired HSP70 Expression in the Aorta of Female Rats: A Novel Insight Into Sex-Specific Differences in Vascular Function.

Heat-shock protein 70 (HSP70) contributes to cellular calcium (Ca2+) handling mechanisms during receptor-mediated vascular contraction. Interestingly, previous studies have independently reported sex-related differences in HSP70 expression and Ca2+ dynamics. Still, it is unknown if sex, as a variable, plays a role in the impact that HSP70 has upon vascular contraction. To narrow this gap, we investigated if differences exist in the expression levels of HSP70 in the aorta, and if targeting this protein contributes to sex disparity in vascular responses. We report that, compared with male animals, female rats present a reduction in the basal levels of HSP70. More compelling, we found that the blockade of HSP70 has a greater impact on phenylephrine-induced phasic and tonic vascular contraction in female animals. In fact, it seems that the inhibition of HSP70 significantly affects vascular Ca2+ handling mechanisms in females, which could be associated with the fact that these animals have impaired HSP70 expression. Corroborating this idea, we uncovered that the higher sensitivity of female rats to HSP70 inhibition does not involve an increase in NO-dependent vasodilation nor a decrease in vascular oxidative stress. In summary, our findings reveal a novel mechanism associated with sex-specific differences in vascular responses to α-1 adrenergic stimulation, which might contribute to unraveling the network of intertwined pathways conferring female protection to (cardio)vascular diseases.

Vascular Responses to First-Generation Sirolimus-Eluting Stents and Bare-Metal Stents Beyond 10 Years.

Background: There are limited data regarding differences in vascular responses between first-generation sirolimus-eluting stents (1G-SES) and bare-metal stents (BMS) >10 years after implantation.Methods and Results: We retrospectively investigated 223 stents (105 1G-SES, 118 BMS) from 131 patients examined by optical coherence tomography (OCT) >10 years after implantation. OCT analysis included determining the presence or absence of a lipid-laden neointima, calcified neointima, macrophage accumulation, malapposition, and strut coverage. Neoatherosclerosis was defined as having lipid-laden neointima. OCT findings were compared between the 1G-SES and BMS groups, and the predictors of neoatherosclerosis were determined. The median stent age at the time of OCT examinations was 12.3 years (interquartile range 11.0–13.2 years). There were no significant differences in patient characteristics between the 1G-SES and BMS groups. On OCT analysis, there was no difference in the prevalence of neoatherosclerosis and calcification between 1G-SES and BMS. Multivariable logistic regression analysis revealed that stent size, stent length, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use were significant predictors of neoatherosclerosis. In addition, uncovered and malapposed struts were more prevalent with 1G-SES than BMS.Conclusions: After >10 years since implantation, the prevalence of neoatherosclerosis was no different between 1G-SES and BMS, whereas uncovered struts and malapposition were significantly more frequent with 1G-SESs.

Attenuated Leg Vascular Conductance Responses To Dynamic Knee Extension Exercise In Young Black Men

Our group recently showed a blunted increase in skeletal muscle vascular conductance and blood flow during rhythmic handgrip exercise in young black (i.e. African American) individuals with no overt cardiovascular diseases compared with white (i.e. Caucasian American) individuals. These findings, along with reduced endothelium‐dependent forearm vasodilation and augmented forearm vasoconstriction to phenylephrine at rest, suggest that vascular alterations occur early in the lifetime of black individuals, possibly predisposing this population to develop cardiovascular diseases. Notably, research on racial differences in vascular responses has almost exclusively examined upper limbs. However, lower limb vascular diseases are more prevalent and cause more adverse events in the black population than in any other racial group in the U.S. Therefore, for a better understanding of racial differences in vascular health, we tested the hypothesis that vascular responses to lower limb exercise would be attenuated in black individuals compared with their white counterparts. Six black (21 ± 1 years; 23 ± 2 kg/m2) and 4 white (21 ± 0 years; 21 ± 1 kg/m2) healthy men performed dynamic knee extension exercise at the workloads of 10, 20, and 30 watts (W) in an upright sitting position on a custom ergometer. Each exercise trial lasted for 3 min with a minimum rest interval of 5 min. Knee extension cadence was 50 repetitions per min, provided by a metronome and real‐time visual feedback. Common femoral artery blood flow (FABF, Doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography) were continuously measured, and leg vascular conductance (LVC) was calculated as FABF/MAP. The participants reported a rating of perceived exertion (Borg Scale 6 – 20) at the end of each trial. Both groups presented LVC increases from rest during dynamic knee extension. While this response was similar between groups at 10 W (White: +1970 ± 138 vs. Black: +1666 ± 173 mL/min/100 mmHg; P = 0.407), the increases in LVC were significantly attenuated in black individuals (mixed‐model ANOVA interaction P = 0.026) at the workloads of 20 W (Whites: +2550 ± 105 vs. Blacks: +1829 ± 179 mL/min/100 mmHg; P = 0.025) and 30 W (Whites: +2528 ± 248 vs. Blacks: +1850 ± 152 mL/min/100 mmHg; P = 0.035). Similarly, FABF responses to dynamic knee extension were lower in black individuals compared with their white counterparts (Interaction P = 0.011). In contrast, increases in MAP were similar between groups (Interaction P = 0.271). The groups reported similar ratings of perceived exertion among trials (Interaction P = 0.817) and achieved similar peak workloads in a dynamic knee extension maximal exercise test (Whites: 48 ± 8 W vs. Blacks: 49 ± 3 W; P = 0.883). These preliminary findings suggest a blunted vasodilator response during leg exercise in black men, further highlighting the early occurrence of vascular alterations in this population.Support or Funding InformationUTA Center of Research and Scholarship Pilot Grant;NIH (1R15HL130906‐01)

Vasoresponsiveness in patients with heart failure (VASOR): protocol for a prospective observational study

BackgroundVasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved.MethodsThis is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with (N = 12) and without heart failure (N = 12).DiscussionUnderstanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome.Trial registrationThe Netherlands Trial Register (NTR), NTR5647. Registered 26 January 2016.

Gender differences in vascular reactivity of mesenteric arterioles in portal hypertensive and non-portal hypertensive rats.

BACKGROUNDPortal hypertension (PHT) is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow. Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome.AIMTo explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats.METHODSCirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride (CCl4) in both male and female integral and castrated rats (ovariectomized [OVX] in female rats, orchiectomy [ORX] in male rats). The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors.RESULTSNo significant difference in portal pressure was observed between integral and castrated male PHT rats (15.2 ± 2.1 mmHg vs 16.7 ± 2.7 mmHg, P > 0.05). The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats (12.7 ± 2.7 mmHg vs 16.5 ± 2.4 mmHg, P < 0.05). In PHT rats, the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right, and the maximal responses (Emax) values were decreased and effective concentrations causing half maximum responses (EC50) values were increased, compared to those of non-PHT rats, both in male and female rats. Compared to non-PHT integral male rats, the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased (P > 0.05). However, there was no difference between integral and ORX male rats with PHT. In integral female PHT rats, the concentration response curves were shifted to the left (P < 0.05), and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats.CONCLUSIONClear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats. Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.

Sex Differences in Vascular Responses to Exercise

Sex Differences in Vascular Responses to Exercise

Sex differences in vascular reactivity in mesenteric arteries from a mouse model of acute intermittent porphyria

Background and aimsAcute intermittent porphyria (AIP) results from a partial deficiency of porphobilinogen deaminase (PBGD). Symptomatic AIP patients, most of whom are women, experience acute attacks characterized by severe abdominal pain and abrupt increases in blood pressure. Here, we characterized the reactivity of mesenteric arteries from male and female AIP mice with ~30% of normal PBGD activity and wild type C57BL/6 mice. MethodsAn acute porphyric attack was induced in AIP mice by treatment with phenobarbital. Vascular responses to K+, phenylephrine (PE), acetylcholine (ACh), and hemin were determined (Wire Multi Myograph). ResultsMaximal contraction to PE was increased in arteries from male and female AIP mice (p < .05) during an induced attack of acute porphyria. Female AIP arteries had increased sensitivity to PE (p < .05) even after nitric oxide (NO) blockade with Nω-nitro-L-arginine methyl ester (L-NAME) (p < .05). Maximal relaxation to ACh was similar in males and females with lower sensitivity in female AIP arteries (p < .05). Hemin induced greater relaxation in AIP arteries in both males and females (p < .05). Summary/conclusionsSex differences in this AIP mouse model include a pro-contractile response in females. These alterations may contribute to the increased blood pressure during an acute attack and provide a novel mechanism of action whereby heme ameliorates the attacks.

Sex difference in GPER expression does not change vascular relaxation or reactive oxygen species generation in rat mesenteric resistance arteries

AimAn imbalance between antioxidant and pro-oxidant factors, with a predominance of the latter, characterises oxidative stress and is indicative of a loss of vascular function. The beneficial vascular effects of oestrogen may be related to its ability to stimulate the G protein-coupled oestrogen receptor (GPER) and produce antioxidant activity. This study evaluated the GPER-dependent relaxation response in the mesenteric resistance arteries of female and male rats and measured the contributions of pro-oxidant and antioxidant enzymes in this response. Main methodsThe relaxation response was characterised in third-order mesenteric arteries using concentration-response curves of the selective GPER agonist G-1 (1 nM–10 μM), target protein levels were measured using Western blots, and vascular superoxide anion (O2−) and hydrogen peroxide (H2O2) levels were measured using dihydroethidium (DHE) and dichlorofluorescein (DCF) staining, respectively. Key findingsThe GPER agonist induced concentration-dependent vasorelaxation without showing differences between sexes. However, GPER expression was greater in male rats. No sex differences were detected in the expression of antioxidant proteins (catalase, SOD-1, and SOD-2). The basal vascular production of O2− and H2O2 was similar in the studied groups, and stimulation with G-1 maintained this response. SignificanceTogether, our results show that the expression of GPER is greater in male mesenteric arteries, despite of the lack of a difference in vascular response. Nevertheless, antioxidant enzyme expression levels and the generation rates of pro-oxidants were similar between the studied groups. These results offer a new perspective for understanding GPER expression and functionality in resistance arteries.

Differences in vascular function between trained and untrained limbs assessed by near-infrared spectroscopy

The aim of this study was to examine whether differences in vascular responsiveness associated with training status would be more prominent in the trained limb (leg) than in the untrained limb(arm) microvasculature. Thirteen untrained (26 ± 5year) and twelve trained (29 ± 4year) healthy men were submitted to a vascular occlusion test (VOT) (2min baseline, 5min occlusion, and 8min re-oxygenation). The oxygen saturation signal (StO2) was assessed using near-infrared spectroscopy (NIRS) throughout the VOT. Vascular responsiveness within the microvasculature was evaluated by the re-oxygenation Slope 2 (Slope 2 StO2) and the area under the curve (StO2AUC) of (StO2) signal during re-oxygenation in the leg and arm. There was a significant interaction between training status and limb for the slope 2 StO2 (P < 0.01). The leg of the trained group showed a steeper slope 2 StO2 (1.35 ± 0.12%s-1) when compared to the slope 2 StO2 of the leg in their untrained counterparts (0.86 ± 0.09%s-1) (P < 0.05). There was a medium effect size of 0.58 for slope 2 StO2 on the arm and a large effect size of 1.21 for slope 2 StO2 on the leg. In addition, there was a small effect size of 0.24 for StO2AUC on the arm and a medium effect size of 0.64 for StO2AUC on the leg. The present study suggests that the vascular adaptations induced by lower limb endurance exercise training are more prominent in the trained limb than in the untrained limb microvasculature.

Inflammation in the subcutaneous adipose tissue does not attenuate endothelial function in subjects with diabetes mellitus and subjects with dyslipidaemia and hypertension: Across-sectional study.

SummaryBackgroundObesity is associated with low‐grade inflammation that may be related to vascular disease. We hypothesized that inflammation in the subcutaneous adipose tissue is associated with impaired endothelium‐dependent vasodilatation.MethodsWe assessed endothelial function by measuring forearm vascular response to acetylcholine and determined inflammation in subcutaneous fat biopsies in 2 groups of subjects; 15 patients with type 2 diabetes mellitus (T2DM) and 19 subjects with dyslipidaemia combined with hypertension (DcH). The adipose tissue inflammation score was based on adipocyte size, influx of macrophages and presence of crown‐like structures. We compared the vascular response to acetylcholine between subjects with and without adipose tissue inflammation.ResultsPatients with diabetes had clearly decreased vasodilatation compared to patients with DcH. In total, 23 of the 34 fulfilled the criteria of subcutaneous adipose tissue inflammation. However, there was no difference in vascular response to acetylcholine between the group with and without inflammation (changes in FBF from baseline 3.9 ± 0.8, 7.8 ± 1.0 and 13.6 ± 1.0 mL/dL/min compared to 4.3 ± 1.0, 7.9 ± 2.1 and 12.2 ± 2.4 mL/dL/min in response to acetylcholine 0.5, 2.0 and 8.0 μg/dL/min), nor was there a relationship between systemic hs‐CRP levels and endothelial function.ConclusionsWe confirm that subjects with T2DM have impaired endothelial function compared to age‐ and BMI‐matched subjects with DcH. However, endothelial function did not differ between participants with or without inflammation in the subcutaneous adipose tissue. These results suggest that fat tissue inflammation, at least in the subcutaneous compartment, does not affect vascular function.

Near-infrared spectroscopy assessment of microvasculature detects difference in lower limb vascular responsiveness in obese compared to lean individuals

BackgroundMicrovascular dysfunction is an early complication in obesity-related cardiovascular disease (CVD) that can lead to changes in hemodynamic function and endothelial cell expression throughout the vasculature that is vessel specific. This study aimed to evaluate whether the near-infrared spectroscopy (NIRS) combined with a vascular occlusion (VOT) assessment was capable of detecting differences in vascular responsiveness within the microvasculature of the lower limb between lean and obese individuals. Methods and resultsTwenty lean (BMI = 21.6 ± 1.3) and 17 obese individuals (BMI = 33.9 ± 1.1) participated in the study. Individuals underwent a VOT (5 min of baseline, 5 min of occlusion, and 8 min following cuff release) and vascular responsiveness was evaluated by the Slope 2 (Slope 2 StO2) and the area under the curve (StO2AUC) of oxygen saturation (StO2) signal during reperfusion. The difference between the minimal and the maximal value of StO2 was calculated as the Amplitude of the StO2 response. The Slope 2 StO2 of the obese individuals was smaller (0.68 ± 0.07%·s−1) than the Slope 2 StO2 of the lean individuals (1.08 ± 0.13%·s−1;P < 0.05). The StO2AUC of the obese was smaller (978 ± 169%·s−1) than the StO2AUC of the lean individuals (1708 ± 168%·s−1; P < 0.001). The amplitude of StO2 was smaller in obese individuals than the lean ones (30.4 ± 2.9 vs 21.6 ± 1.3 StO2 (%), respectively; P < 0.05). There was a significant correlation between Slope 2 StO2 and StO2AUC for lean individuals (r = 0.745; P < 0.001). ConclusionThis study demonstrated differences in vascular responses within the microvasculature of the lower limb between lean and obese individuals.

Etiology of language network changes during recovery of aphasia after stroke

Knowledge of spatiotemporal patterns of language network changes may help in predicting outcome in aphasic stroke patients. Here we assessed language function and performed functional MRI four times during one year to measure language network activation and cerebrovascular reactivity (with breath-holding) in twelve left-hemispheric stroke patients, of whom two dropped out before the final measurement, and eight age-matched controls. Language outcome was related to increase of activation in left and right posterior inferior temporal gyrus over the first year, while activation increase in right inferior frontal gyrus was inversely correlated to language recovery. Outcome prediction improved by addition of early language-induced activation of the left posterior inferior temporal gyrus to a regression model with baseline language performance as first predictor. Variations in language-induced activation in right inferior frontal gyrus were primarily related to differences in vascular reactivity. Furthermore, several language-activation changes could not be linked to alterations in language proficiency nor vascular reactivity, and were assumed to be caused by unspecified intersession variability. In conclusion, early functional neuroimaging improves outcome prediction of aphasia after stroke. Controlling for cerebrovascular reactivity and unspecified intersession variability may result in more accurate assessment of the relationship between activation pattern shifts and function after stroke.