Ion Channels Remodeling in the Regulation of Vascular Hyporesponsiveness During Shock.

Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K+ channels, Ca2+ permeable channels, and Na+ channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel-targeted compounds in treating refractory hypotension in shock.

Evaluating cerebrovascular reactivity measured by velocity selective inversion arterial spin labeling with different post-labeling delays: The effect of fast flow.

PURPOSE: Velocity selective arterial spin labeling (VSASL) quantification assumes that the labeled bolus continuously moves into the imaging voxel during the post-labeling delay (PLD). Faster blood flow could lead to a bolus duration shorter than the applied PLD of VSASL and cause underestimation of cerebral blood flow (CBF). This study aims to evaluate the performance of velocity-selective inversion (VSI) prepared arterial spin labeling (ASL) with different PLDs and pseudo-continuous ASL (PCASL) for quantification of hypercapnia-induced cerebrovascular reactivity (CVR), using phase-contrast (PC) MRI as a global reference. METHODS: We compared CVR obtained by VSI-ASL with PLD of 1520 ms (VSASL-1520), 1000 ms (VSASL-1000), and 500 ms (VSASL-500), PCASL with PLD of 1800 ms (PCASL-1800), and PC MRI on eight healthy volunteers at two sessions. RESULTS: Compared with PC MRI, VSASL-1520 produced significantly lower global CVR values, while PCASL-1800, VSASL-1000, and VSASL-500 yielded more consistent results. The reduced CVR in VSASL-1520 was more pronounced in carotid territories including frontal and temporal lobes than in vertebral territories such as the occipital lobe. This is largely caused by the underestimated perfusion during hypercapnia due to the reduced bolus duration being less than the PLD. CONCLUSION: Although VSASL offers certain advantages over spatially selective ASL due to its reduced susceptibility to delayed ATT, this technique is prone to biases when the ATT is excessively short. Therefore, a short PLD should be employed for reliable perfusion and CVR quantification in populations or conditions with fast flow.

Cerebral Vasomotor Reactivity to Carbon Dioxide Using the Rebreathe Technique: Assessment of Within-day and Between-day Repeatability.

The cerebral vasodilator response to increased arterial carbon dioxide (CO2) concentration, termed cerebral vasomotor reactivity (CVMR), is used to assess cerebral vascular function. We sought to assess the within-day and between-day repeatability of CVMR to rebreathing-induced hypercapnia. Twelve healthy adults performed a within-day short interval protocol (17±2 minutes between trials), ten performed a within-day long interval protocol (145±16 minutes between trials), and seventeen performed a between-day protocol (5±2 days between visits). Repeatability of the slope of the percent change in middle cerebral artery mean blood velocity (%MCAvmean) and cerebral vascular conductance index (%CVCi), to the change in partial pressure of end-tidal CO2 (PETCO2) between the two trials/days was assessed. Within-day short interval %MCAvmean slope demonstrated fair to excellent repeatability (intraclass correlation, ICC=0.92 [95% confidence interval 0.72-0.98]; p<0.001) while %CVCi slope showed more variability (ICC=0.84 [0.47-0.95]; p=0.002]). Within-day long interval, %MCAvmean (ICC=0.95 [0.80-0.99]) and %CVCi (ICC=0.94 [0.71-0.99]) slopes showed good to excellent and fair to excellent repeatability respectively (p<0.001 for both). For between-day trials, better repeatability was observed for %CVCi (ICC=0.85 [0.57-0.95]; p<0.001) compared to %MCAvmean (ICC=0.76 [0.33-0.91]; p=0.004) slope. These findings indicate repeatable within- and between-day CVMR responses to rebreathe induced hypercapnia. However, a longer interval may be better for within-day repeat trials, particularly for CVCi measures.

Maternal exposure to glyphosate-based herbicide causes vascular dysfunction in offspring female rats.

This study analyzed how glyphosate exposure in the gestational period affects vascular function in their female offspring and whether oxidative stress is involved in this effect. To this, pregnant Wistar rats were exposed through drinking water to 0.2% of a glyphosate commercial formulation, and we analyzed the response to acetylcholine and phenylephrine in the aorta from offspring of Glyphosate-based herbicide (O-GBH) and controls (O-CON) rats at six months of age. Relaxation to acetylcholine was reduced in O-GBH than in O-CON. Acute Indomethacin and Apocynin increased relaxation to acetylcholine in O-GBH. The aorta from O-GBH was hyperactive to phenylephrine; the preincubation with N-nitro-L-arginine methyl ester (L-NAME) increased contraction to phenylephrine more in O-CON than O-GBH. TEMPOL similarly reduced phenylephrine response, and L-NAME prevented this effect. The TBARS and GSH levels were increased in O-GBH than in O-CON. Results reinforce the concept that oxidative stress during the perinatal period contributes to the development of vascular changes in adulthood. Results also reveal that oxidative stress parameters altered, and the current levels considered safe for exposure to Glyphosate deserve further investigation, especially in the female gender.

Serum N-Terminal Pro-B-Type Natriuretic Peptide Level is Negatively Associated with Vascular Reactivity Index by Digital Thermal Monitoring in Patients with Hypertension.

Background: B-type natriuretic peptide (BNP) coordinates endothelial homeostasis and remodeling, with endothelial dysfunction associated with cardiovascular mortality in the general population without heart failure. The objective of this study was to investigate the correlation between serum N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels and endothelial dysfunction among patients diagnosed with hypertension. Methods: This cross-sectional, single-center study included 90 patients with hypertension. An electrochemiluminescence immunoassay measured NT-pro-BNP levels, and a digital thermal monitoring device calculated a vascular reactivity index (VRI) as a measurement for endothelial function. In this study, VRI < 1.0 denoted poor vascular reactivity, 1.0 ≤ VRI < 2.0 indicated intermediate vascular reactivity, and a VRI ≥ 2.0 suggested good vascular reactivity. Results: Out of all the hypertensive patients, eight (8.9%) displayed poor vascular reactivity (VRI < 1.0), while 39 (43.3%) exhibited intermediate vascular reactivity (1.0 ≤ VRI < 2.0), leaving the remaining 43 patients demonstrating good vascular reactivity. Older age (p = 0.012) and elevated serum NT-pro-BNP levels (p < 0.001) were found to be associated with poorer vascular reactivity. Older age (r = -0.221, p = 0.036) and log-transformed serum levels of NT-pro-BNP (log-NT-pro-BNP, r = -0.505, p < 0.001) exhibited a negative correlation with VRI values in patients with hypertension. Following a multivariate linear regression test, serum log-NT-pro-BNP level ( ß = -0.505, adjusted R 2 change = 0.246, p < 0.001) emerged as being significantly and independently associated with VRI values among hypertensive patients. Conclusions: In patients with hypertension, there was a negative association observed between serum log-NT-pro-BNP levels and endothelial dysfunction determined by VRI values.

Non-invasive in-utero quantification of vascular reactivity in human placenta.

OBJECTIVE: Placental vascular reactivity (PlVR) indicates the ability of the placental vasculature to match blood supply to fetal demand. Many pregnancy disorders alter the characteristics of PlVR, resulting in suboptimal oxygen delivery, although current understanding is limited by the lack of non-invasive, repeatable methods to measure PlVR in utero. Our objective was to quantify PlVR by measuring the placental response to transient changes in maternal carbon dioxide (CO2) using blood-oxygen-level-dependent (BOLD) magnetic resonance imaging (MRI). We hypothesized that PlVR will increase with gestational age to meet the changing demands of a growing fetus, and that PlVR will be driven by a maternal response to changes in CO2 concentration. METHODS: This was a cross-sectional study of 35 women with a healthy singleton pregnancy, of whom 31 were included in the analysis. The median gestational age was 32.6 (range, 22.6-38.4) weeks. Pregnant women were instructed to follow audiovisual breathing cues during a MRI scan. Maternal end-tidal CO2 (EtCO2) was measured concurrently with resting placental BOLD MRI for a total of 7-8 min. Preprocessing of magnetic resonance images consisted of manual delineation of placental anatomy and motion correction. In each placental voxel, vascular reactivity was computed using a coherence-weighted general linear model between MRI signal and EtCO2 stimulus. Global PlVR was computed as the mean of voxel-wise PlVR values across the placenta. RESULTS: PlVR, quantified by the placental response to induced, transient changes in maternal CO2, was consistently measured in utero using BOLD MRI. PlVR increased non-linearly with advancing gestational age (P < 0.001) and was higher on the fetal side of the placenta. PlVR was associated positively with fetal brain volume after accounting for gestational age. PlVR did not show any significant associations with maternal characteristics. CONCLUSIONS: We present, for the first time, a non-invasive paradigm to quantify PlVR in ongoing human pregnancies without the use of exogenous gases or contrast agents. Our findings suggest that PlVR is driven by a fetal response to changes in maternal CO2. Ease of translation to the clinical setting makes PlVR a promising biomarker for the identification and management of high-risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Vascular Reactivity Index as an Effective Predictor of Mortality in Patients With Septic Shock: A Retrospective Study.

BACKGROUND: Sepsis is a serious complication that occurs after trauma, burns, and infections, and it is an important cause of death in intensive care unit (ICU) patients. Despite many new measures being proposed for sepsis treatment, its mortality rate remains high; sepsis has become a serious threat to human health, and there is an urgent need to carry out in-depth clinical research related to sepsis. In recent years, it has been found that septic shock-induced vasoplegia is a result of vascular hyporesponsiveness to vasopressors. Therefore, this study intended to establish an objective formula related to vasoplegia that can be used to assess the prognosis of patients and guide clinical treatment. MATERIALS AND METHODS: A retrospective cohort study was conducted using data from 106 septic shock patients admitted to the ICU of Jining No. 1 People's Hospital from January 2020 to December 2022. The patients were divided into mortality and survival groups based on 28-day survival, and hemodynamics were monitored by the pulse index continuous cardiac output system. The dose and duration of vasopressors, major hemodynamic parameters, lactic acid (Lac) levels, and Sequential Organ Failure Assessment scores were recorded within 48 h of hospital admission. Multifactorial logistic regression was used to analyze the independent risk factors affecting the prognosis of patients, and the predictive value of the vascular response index (VRI) was analyzed by the receiver operating characteristic (ROC) curve. RESULTS: The differences between the survival and mortality groups in terms of age, sex ratio, body weight, ICU length of stay, distribution of infection sites, underlying disease conditions, baseline Lac levels, and some hemodynamic parameters were not statistically significant (P > .05). The results of multifactorial logistic regression showed that the admission Acute Physiology and Chronic Health Evaluation II score, Lac level at 24 h of treatment, maximal vasoactive inotropic score at 24 h (VISmax24), maximal vasoactive inotropic score at 48 h (VISmax48), and VRI were independent risk factors affecting 28-day mortality. Within 48 h of receiving vasopressor therapy, the VRI was lower in the mortality group than in the survival group. The area under the ROC curve for the VRI was 0.86, and the best cutoff value of the VRI for predicting 28-day mortality was 32.50 (YI = 0.80), with a sensitivity of 0.90, a specificity of 0.90, and a better prediction of mortality than the other indicators. CONCLUSIONS: The VRI is a good predictor of mortality in patients with septic shock, and a lower VRI indicates more severe vasoplegia, poorer prognosis, and higher mortality in patients with septic shock.

Long-term prognostic value of [15O]H2O PET imaging in patients suspected for cerebral hemodynamic insufficiency.

OBJECTIVES: Quantitative regional cerebral perfusion (rCBF) measurements using [15O]H2O PET with arterial cannulation and acetazolamide (ACZ) challenge have been reserved to identify high-risk patients that are candidates for by-pass operation. We aimed to assess the prognostic value of various parameters in quantitative [15O]H2O PET measurements in patients not subsequently undergoing surgery. METHODS: We identified 32 eligible patients who underwent [15O]H2O brain PET imaging for suspicion of hemodynamic insufficiency between 2009 and 2020. Cerebrovascular events were defined as new ischemic lesions on MRI, stroke, transient ischemic attack, vascular dementia. Follow-up period was 91 months (range: 26-146). rCBF before (rCBFbase) and after (rCBFacz) ACZ challenge and the relative increase (CVR), were examined in the anterior (ACA), middle (MCA), and posterior (PCA) cerebral artery territories of the affected hemisphere, and the most recent MRI scans were scored for infarcts and white matter lesions. RESULTS: Receiver operating characteristic (ROC) curve analysis showed higher prognostic accuracy for rCBFacz(AUC:0.82) compared to CVR (AUC:0.72) and rCBFbase (AUC:0.77). ROC AUC, optimal thresholds (and corresponding sensitivity/specificity/accuracy) for rCBFacz after ACZ in individual territories were 0.79 and 37.8 mL 100g-1 min-1 (0.81/0.63/0.72) for the ACA, 0.84 and 32 mL 100g-1 min-1 (0.81/0.75/0.78) for the MCA, and 0.70 and 43.9 ml/(mL 100g-1 min-1 (0.81/0.43/0,62) for the PCA. Kaplan Meier survival curve showed longer event-free survival in patients with rCBFacz below cut-off (p=0.007). In multivariate analysis rCBFacz remained a significant predictor when correcting for age. CONCLUSION: Quantitative rCBF measurements after ACZ challenge with [15O]H2O PET provided high prognostic value for future cerebrovascular events.

Methamphetamine-Induced Blood Pressure Sensitization Correlates with Morphological Alterations within A1/C1 Catecholamine Neurons.

Methamphetamine (METH) is a drug of abuse, which induces behavioral sensitization following repeated doses. Since METH alters blood pressure, in the present study we assessed whether systolic and diastolic blood pressure (SBP and DBP, respectively) are sensitized as well. In this context, we investigated whether alterations develop within A1/C1 neurons in the vasomotor center. C57Bl/6J male mice were administered METH (5 mg/kg, daily for 5 consecutive days). Blood pressure was measured by tail-cuff plethysmography. We found a sensitized response both to SBP and DBP, along with a significant decrease of catecholamine neurons within A1/C1 (both in the rostral and caudal ventrolateral medulla), while no changes were detected in glutamic acid decarboxylase. The decrease of catecholamine neurons was neither associated with the appearance of degeneration-related marker Fluoro-Jade B nor with altered expression of α-synuclein. Rather, it was associated with reduced free radicals and phospho-cJun and increased heat shock protein-70 and p62/sequestosome within A1/C1 cells. Blood pressure sensitization was not associated with altered arterial reactivity. These data indicate that reiterated METH administration may increase blood pressure persistently and may predispose to an increased cardiovascular response to METH. These data may be relevant to explain cardiovascular events following METH administration and stressful conditions.

Impact of region of interest definition on visual stimulation-based cerebral vascular reactivity functional MRI with a special focus on applications in cerebral amyloid angiopathy.

Cerebral vascular reactivity quantified using blood oxygen level-dependent functional MRI in conjuncture with a visual stimulus has been proven to be a potent and early marker for cerebral amyloid angiopathy. This work investigates the influence of different postprocessing methods on the outcome of such vascular reactivity measurements. Three methods for defining the region of interest (ROI) over which the reactivity is measured are investigated: structural (transformed V1), functional (template based on the activation of a subset of subjects), and percentile (11.5 cm3 most responding voxels). Evaluation is performed both in a test-retest experiment in healthy volunteers (N = 12), as well as in 27 Dutch-type cerebral amyloid angiopathy patients and 33 age- and sex-matched control subjects. The results show that the three methods select a different subset of voxels, although all three lead to similar outcome measures in healthy subjects. However, in (severe) pathology, the percentile method leads to higher reactivity measures than the other two, due to circular analysis or "double dipping" by defining a subject-specific ROI based on the strongest responses within each subject. Furthermore, while different voxels are included in the presence of lesions, this does not necessarily result in different outcome measures. In conclusion, to avoid bias created by the method, either a structural or a functional method is recommended. Both of these methods provide similar reactivity measures, although the functional ROI appears to be less reproducible between studies, because slightly different subsets of voxels were found to be included. On the other hand, the functional method did include fewer lesion voxels than the structural method.

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

AIMS: 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. METHODS AND RESULTS: 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 ß2 adrenoceptors; M1, M2, and M3 muscarinic receptors; and bradykinin (BKR) and thromboxane-prostanoid (TP) receptors, through bioinformatics tools; ii) expression of α1, ß2, 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. CONCLUSIONS: 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. TRANSLATIONAL PERSPECTIVE: 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.

Vascular adaptation to cancer beyond angiogenesis: The role of PTEN.

Cancer is a public health problem, and it needs blood vessels to grow. Knowing more about the processes of vascular adaptation to cancer improves our chances of attacking it, since the tumor for its extension needs such adaptation to satisfy its progressive demand for nutrients. The main objective of this review is to present the reader with some fundamental molecular pathways for vascular adaptation to cancer, highlighting within them the regulatory role of homologous tensin and phosphatase protein (PTEN). Hence the review describes vascular adaptation to cancer through somewhat known processes, such as angiogenesis, but emphasizes others that are much less explored, namely the changes in vascular reactivity and remodeling of the vascular wall -intima-media thickness and adjustments in the extracellular matrix- The role of PTEN in physiological and pathological vascular mechanisms in different types of cancer is deepened, as a crucial mediator in vascular adaptation to cancer, and points pending further exploration in cancer vascularization are suggested.

Microvascular effects of oxygen and carbon dioxide measured by vascular occlusion test in healthy volunteers.

BACKGROUND: Changes in near-infrared spectroscopy-derived regional tissue oxygen saturation (StO2) during a vascular occlusion test (VOT; ischemic provocation of microcirculation by rapid inflation and deflation of a tourniquet) allow estimating peripheral tissue O2 consumption (desaturation slope; DS), vascular reactivity (recovery slope; RS) and post-ischemic hyperperfusion (AUC-H). The effects of isolated alterations in the inspiratory fraction of O2 (FiO2) and changes in expiratory CO2 remain to be elucidated. Therefore, in this secondary analysis we determined the effects of standardized isolated instances of hypoxia, hyperoxia, hypocapnia and hypercapnia on the VOT-induced StO2 changes in healthy volunteers (n = 20) to establish reference values for future physiological studies. METHODS: StO2 was measured on the thenar muscle. Multiple VOTs were performed in a standardized manner: i.e. at room air (baseline), during hyperoxia (FiO2 1.0), mild hypoxia (FiO2 ≈ 0.11), and after a second baseline, during hypocapnia (end-tidal CO2 (etCO2) 2.5-3.0 vol%) and hypercapnia (etCO2 7.0-7.5 vol%) at room air. Differences in DS, RS, and AUC-H were tested using repeated-measures ANOVA. RESULTS: DS and RS remained constant during all applied conditions. AUC-H after hypoxia was smaller compared to hyperoxia (963 %*sec vs hyperoxia 1702 %*sec, P = 0.005), while there was no difference in AUC-H duration between hypoxia and baseline. The StO2 peak (after tourniquet deflation) during hypoxia was lower compared to baseline and hyperoxia (92 % vs 94 % and 98 %, P < 0.001). CONCLUSION: We conclude that in healthy volunteers at rest, common situations observed during anesthesia and intensive care such as exposure to hypoxia, hyperoxia, hypocapnia, or hypercapnia, did not affect peripheral tissue O2 consumption and vascular reactivity as assessed by VOT-induced changes in StO2. These observations may serve as reference values for future physiological studies. TRIAL REGISTRATION: This study represents a secondary analysis of an original study which has been registered at ClinicalTrials.gov nr: NCT02561052.

Role of the iNOS isoform in the cardiovascular dysfunctions of male rats with 6-OHDA-induced Parkinsonism.

INTRODUCTION: Available studies have shown the involvement of nitric oxide (NO) in the processes that lead to neurodegeneration in Parkinson's disease (PD). Also, the use of inhibitors of the inducible isoform of NO-synthase (iNOS) promotes neuroprotection and attenuates dopamine (DA) loss in experimental models of Parkinsonism. In addition, NO also appears to be involved in cardiovascular changes in 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. The current study aimed to evaluate the effects of iNOS inhibition on cardiovascular and autonomic function in animals that were subjected to Parkinsonism by the administration of 6-OHDA. MATERIALS AND METHODS: The animals underwent stereotaxic surgery for bilateral microinfusion of the neurotoxin 6-OHDA (6 mg/mL in 0.2% ascorbic acid in sterile saline solution) or vehicle solution for the Sham group. From the day of stereotaxis until the day of femoral artery catheterization, the animals were treated with the iNOS inhibitor, S-methylisothiourea (SMT; 10 mg/kg; i. p.) or saline solution (0.9%; i. p.) for 7 days. The animals were divided into four groups: Sham-Saline, Sham-SMT, 6-OHDA-Saline, and 6-OHDA-SMT. Subsequent analyses were performed on these four groups. After 6 days, they underwent catheterization of the femoral artery, and 24 h later, mean arterial pressure (MAP) and heart rate (HR) were recorded. Another group of animals (the 6-OHDA and Sham groups) was assessed for aortic vascular reactivity after 7 days of bilateral infusion of 6-OHDA or vehicle, in which cumulative concentration-effect curves (CCEC) were made for phenylephrine (Phenyl), acetylcholine and sodium nitroprusside (NPS). Also, CCEC in the presence of Nw-nitro-arginine-methyl-ester (l-NAME) (10-5 M), SMT (10-6 M), and indomethacin (10-5 M) blockers were made. RESULTS: The effectiveness of the 6-OHDA lesion was confirmed with the reduction of DA in 6-OHDA animals. However, treatment with SMT could not reverse the loss of DA. Concerning the baseline parameters, SBP and MAP values were lower in 6-OHDA animals compared to their Sham control, with no effect of treatment with SMT. In the analysis of SBP variability, a decrease in variance, the VLFabs component, and the LFabs component were observed in the 6-OHDA groups when compared to their controls, regardless of treatment with SMT. It was also observed that intravenous injections of SMT resulted in an increase in BP and a decrease in HR. However, the response was not different between the Sham and 6-OHDA groups. In vascular function, there was a hyporeactivity to Phenyl in the 6-OHDA group, and when investigating the mechanisms of this hyporeactivity, it was seen that the Rmax to Phenyl increased with incubation with SMT, indicating that iNOS could be involved in the vascular hyporeactivity of animals with Parkinsonism. CONCLUSION: Thus, the set of results presented in this study suggests that part of the cardiovascular dysfunction in animals subjected to 6-OHDA Parkinsonism may be peripheral and involve the participation of endothelial iNOS.

In vitro cadmium exposure induces structural damage and endothelial dysfunction in female rat aorta.

Cadmium is a heavy metal that is widespread in the environment and has been described as a metalloestrogen and a cardiovascular risk factor. Experimental studies conducted in male animals have shown that cadmium exposure induces vascular dysfunction, which could lead to vasculopathies caused by this metal. However, it is necessary to investigate the vascular effects of cadmium in female rats to understand its potential sex-dependent impact on the cardiovascular system. While its effects on male rats have been studied, cadmium may act differently in females due to its potential as a metalloestrogen. In vitro studies conducted in a controlled environment allow for a direct assessment of cadmium's impact on vascular function, and the use of female rats ensures that sex-dependent effects are evaluated. Therefore, the aim of this study was to investigate the in vitro effects of Cadmium Chloride (CdCl2, 5 µM) exposure on vascular reactivity in the isolated aorta of female Wistar rats. Exposure to CdCl2 damaged the architecture of the vascular endothelium. CdCl2 incubation increased the production and release of O2•-, reduced the participation of potassium (K+) channels, and increased the participation of the angiotensin II pathway in response to phenylephrine. Moreover, estrogen receptors alpha (Erα) modulated vascular reactivity to phenylephrine in the presence of cadmium, supporting the hypothesis that cadmium could act as a metalloestrogen. Our results demonstrated that in vitro cadmium exposure induces damage to endothelial architecture and an increase in oxidative stress in the isolated aorta of female rats, which could precipitate vasculopathies. Graphical Abstract. Own source from Canva and Servier Medical Art servers.

Salt Restriction and Angiotensin-Converting Enzyme Inhibitor Improve the Responsiveness of the Small Artery in Salt-Sensitive Hypertension.

For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of resistance arteries is unclear. Here, we present an intravital study to detect the effect of salt restriction and ACE inhibitors on the function of the mesenteric small artery (MSA) in SSH. Dahl salt-sensitive rats were randomized into the following groups: ACE inhibitor gavage, salt restriction, ACE inhibitor combined with salt restriction, and high-salt diet. After a 12-week intervention, the mesenteric vessels maintained their perfusion in vivo, and the changes in the diameter and blood perfusion of the MSAs to norepinephrine (NE) and acetylcholine (ACh) were detected. Switching from a high-salt diet to a low-salt diet (i.e., salt restriction) attenuated the vasoconstriction of the MSAs to NE and promoted the vasodilatation to ACh, while ACE inhibitor improved the vasodilatation more obviously. Pathologically, changes in local ACE, AT1R, and eNOS expression were involved in these processes induced by a high-salt diet. Our study suggests that salt restriction and ACE inhibitor treatment improve high salt intake-induced MSA dysfunction in SSH, and salt restriction is a feasible and effective treatment. Our findings may provide a scientific basis for the treatment of hypertension.

Chronic intermittent hypobaric hypoxia ameliorates vascular reactivity through upregulating adiponectin expression of PVAT in metabolic syndrome rats.

Cumulating evidence demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had beneficial effects on the body. This study investigated the role of perivascular adipose tissue (PVAT) in ameliorating effect of CIHH on vascular reactivity by adiponectin in mesenteric artery of metabolic syndrome (MS) rats. Main methods: 6-week-old male Sprague-Dawley rats were randomly divided into four groups: control (CON), MS model, CIHH treatment, and MS + CIHH treatment group. The size of adipocytes in PVAT was measured by scanning electron microscopy. Serum adiponectin was measured. The microvessel recording technique was used to observe the effect of CIHH on contraction and relaxation in mesenteric artery rings. Also, the expressions of interleukin-1ß, tumor necrosis factor-α, adiponectin, AdipoR1, AdipoR2, APPL1, and endothelial nitric oxide synthase (eNOS) were assayed by Western blotting. Key findings: in MS rats, adipocyte size increased, serum adiponectin decreased, contraction reaction increased while relaxation reaction decreased, the expression of pro-inflammatory cytokines was upregulated, while adiponectin was downregulated in PVAT, and the expressions of AdipoR1, AdipoR2, APPL, and phosphorylated-eNOS were downregulated in mesenteric artery. All aforementioned abnormalities of MS were ameliorated in MS + CIHH rats. We concluded that CIHH treatment improves vascular reactivity through upregulating adiponectin expression and downregulating pro-inflammatory cytokine expression of PVAT in MS rats.

Glucose 6-P Dehydrogenase Overexpression Improves Aging-Induced Endothelial Dysfunction in Aorta from Mice: Role of Arginase II.

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6-9 months), old WT (21-22 months) and old G6PD-Tg (21-22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing G6PD underexpressed arginase II and also displayed a lower activity of this enzyme. Moreover, histological analyses demonstrated that age causes a thickness of aortic walls, but this did not occur in G6PD-Tg mice. We conclude that the overexpressing G6PD mouse is a model to improve vascular health via the arginase pathway.

Serum Osteoprotegerin Levels and the Vascular Reactivity Index in Patients with Hypertension.

Background and Objectives: Osteoprotegerin (OPG), a soluble glycoprotein found in serum, has been associated with both the presence and severity of atherosclerosis. OPG is regarded as the mediator in the process of vascular endothelial dysfunction. Impaired endothelial function has an intimate link with hypertension (HTN) and is associated with significant morbidity and mortality. This study was to investigate the connection between OPG and endothelial dysfunction in patients having HTN. Materials and Methods: There are 102 patients with HTN included. For the purpose of determining the levels of OPG, a commercial enzyme-linked immunosorbent test kit was applied. The vascular reactivity index (VRI), which is assessed via the digital thermal monitoring, provides information on endothelial function. Results: Ten patients with HTN (9.8%) were classified as having poor vascular reactivity (VRI < 1.0), 46 HTN patients (45.1%) as having intermediate vascular reactivity (1.0 ≤ VRI < 2.0), and 46 HTN patients (45.1%) were classified as having high vascular reactivity (VRI ≥ 2.0). A greater serum OPG level (p < 0.001) and older age (p = 0.022) were linked to impaired vascular reactivity. The estimated glomerular filtration rate (r = 0.196, p = 0.048) was positively correlated with VRI values in hypertensive participants, while advanced age (r = -0.222, p = 0.025) and the log-transformed OPG level (log-OPG, r = -0.357, p < 0.001) were negatively correlated with VRI. Serum log-OPG level was shown to be strongly and independently correlated with VRI values in HTN individuals after multivariable forward stepwise linear regression analysis (ß = -0.357, adjusted R2 change = 0.119, p < 0.001). Conclusions: In patients with HTN, serum OPG levels were adversely correlated with VRI and probably had a role in endothelial dysfunction.

Exosomes facilitate intercellular communication between uterine perivascular adipose tissue and vascular smooth muscle cells in pregnant rats.

Perivascular adipose tissue (PVAT) is distinct from other adipose depots, as it has differential gene and protein profiles and vasoactive functions. We have shown that pregnancy affects the morphology of PVAT surrounding the uterine arteries (utPVAT) differentially than the morphology of nonperivascular reproductive adipose depots (i.e., periovarian adipose tissue, OVAT). Here, we hypothesized that pregnancy modifies the profile (size and molecular mass) of exosome-like extracellular vesicles released by utPVAT (Exo-utPVAT) compared with exosome-like extracellular vesicles released by OVAT (Exo-OVAT) and that primary uterine vascular smooth muscle cells (utVSMCs) can internalize Exo-utPVAT. Our findings indicate that utPVAT from pregnant and nonpregnant rats secrete exosome-like vesicles. Exo-utPVAT from pregnant rats were smaller (i.e., molecular size) and heavier (i.e., molecular mass) than those from nonpregnant rats, whereas pregnancy did not affect the size of Exo-OVAT. Immunocytochemistry and confocal microscopy showed that primary utVSMCs internalized Exo-utPVAT (both tissues from the same pregnant rat) labeled by the lipophilic tracer DiO. Treatment of isolated uterine arteries with Exo-utPVAT did not affect relaxation responses to acetylcholine in pregnant or nonpregnant rats. Collectively, these findings demonstrate a novel type of intercellular communication between Exo-utPVAT and utVSMCs and indicate pregnancy modulates the morphology and cargo of Exo-utPVAT.NEW & NOTEWORTHY Uterine perivascular adipose tissue secretes exosome-like vesicles, which are internalized by their adjacent uterine vascular smooth muscle cells. Consideration of the exosomal communication between adipose tissue and vascular smooth muscle cells in the uterine circulation in mathematical models and experimental designs may help us to improve understanding of mechanisms underlying uterine artery adaptive responses to a healthy pregnancy and during pregnancy complications.