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Progesterone seems to play a role in cardiovascular physiology since its receptors are expressed on endothelial cells from both sexes of mammals. However, little is known about its role on the coronary circulation. Thus, this study ai ms to evaluate the effect of acute administration of progesterone on the coronary bed and the endothelial pathways involved in this action in normotensive rats of both s exes. A dose-response curve of progesterone (1-50 µmol/L) in isolated hearts using the Langendorff preparation was performed. Baseline coronary perfusion pressure (CPP) was determined, and the vasoactive effect of progesterone was evaluated before and after infusion with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin, catalase, and Tiron. The analysis of nitric oxide (NO) and superoxide anion (O2 ·-) was performed by DAF-2DA and DHE, respectively. Female group showed higher CPP. Nevertheless, progesterone promoted a similar relaxing response in both sexes. The use of L-NAME increased va sodilatory response in both sexes. When indomethacin was used, only the males showed a reduced relaxing response, and in the combined inhibition with L-NAME, indomethacin, and catalase, or with the use of Tiron, only the females presented reduced re sponses. NO and O2 ·-production has increased in female group, while the male group has increased only NO production. Our results suggest that progesterone is able to modulate vascular reactivity in coronary vascular bed with a vasodilatory response in both s exes. These effects seem to be, at least in part, mediated by different endothelial pathw ays, involving NO and EDH pathways in females and NO and prostanoids pathways in males. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory response syndrome (SIRS) resulting from a severe infection that is characterized by immune dysregulation, cardiovascular derangements, and end-organ dysfunction. The modification of proteins by O -linked N-acetylglucosamine (O -GlcNAcylation) influences many of the key processes that are altered during sepsis, including the production of inflammatory mediators and vascular contractility. Here, we investigated whether O -GlcNAc affects the inflammatory response and cardiovascular dysfunction associated with sepsis. Mice received an intraperitoneal injection of lipopolysaccharide (LPS, 20 mg/Kg) to induce endotoxic shock and systemic inflammation, resembling sepsis-induced SIRS. The effects of an acute increase in O -GlcNAcylation, by treatment of mice with glucosamine (GlcN, 300 mg/Kg, i.v.) or thiamet-G (ThG, 150 μg/Kg, i.v.), on LPS-associated mortality, production and release of cytokines by macrophages and vascular cells, vascular responsiveness to constrictors and blood pressure were then determined. Mice under LPS-induced SIRS exhibited a systemic and local inflammatory response with increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), as well as severe hypotension and vascular hyporesponsiveness, characterized by reduced vasoconstriction to phenylephrine. In addition, LPS increased neutrophil infiltration in lungs and produced significant lethality. Treatment with GlcN and ThG reduced systemic inflammation and attenuated hypotension and the vascular refractoriness to phenylephrine, improving survival. GlcN and ThG also decreased LPS-induced production of inflammatory cytokines by bone marrow-derived macrophages and nuclear transcription factor-kappa B (NF-κB) activation in RAW 264.7 NF-κB promoter macrophages. Treatment of mice with ThG increased O -glycosylation of NF-κB p65 subunit in mesenteric arteries, which was associated with reduced Ser536 phosphorylation of NF-κB p65. Finally, GlcN also increased survival rates in mice submitted to cecal ligation and puncture (CLP), a sepsis model. In conclusion, increased O -GlcNAc reduces systemic inflammation and cardiovascular disfunction in experimental sepsis models, pointing this pathway as a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Previously, we showed that 6β-hydroxytestosterone (6β-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to angiotensin II (Ang II)-induced hypertension in male mice. This study was conducted to test the hypothesis that 6β-OHT contributes to increased vascular reactivity, endothelial dysfunction, vascular hypertrophy, and reactive oxygen species production associated with Ang II-induced hypertension. Methods: Eight- to 10-week-old intact or castrated C57BL/6 J (Cyp1b1+/+ and Cyp1b1−/−) mice were anesthetized for implantation of a micro-osmotic pump which delivered Ang II (700 ng/kg/day) or saline for 14 days. Mice were injected with 6β-OHT (15 μg/g b.w every third day), flutamide (8 mg/kg every day), or its vehicle. Blood pressure was measured via tail-cuff. Vascular reactivity, endothelial-dependent and endothelial-independent vasodilation, media to lumen ratio, fibrosis by collagen deposition, and reactive oxygen species production by dihydroethidium staining were determined in the isolated thoracic aorta. Results: The response of thoracic aorta to phenylephrine and endothelin-1 was increased in Ang II-infused Cyp1b1+/+ mice compared to intact Cyp1b1−/− or castrated Cyp1b1+/+ and Cyp1b1−/− mice; these effects of Ang II were restored by treatment with 6β-OHT. Ang II infusion caused endothelial dysfunction, as indicated by decreased relaxation of the aorta to acetylcholine in Cyp1b1+/+ but not Cyp1b1−/− or castrated Cyp1b1+/+ and Cyp1b1−/− mice. 6β-OHT did not alter Ang II-induced endothelial dysfunction in Cyp1b1+/+ mice but restored it in Cyp1b1−/− or castrated Cyp1b1+/+ and Cyp1b1−/− mice. Ang II infusion increased media to lumen ratio and caused fibrosis and reactive oxygen species production in the aorta of Cyp1b1+/+ mice. These effects were minimized in the aorta of Cyp1b1−/− or castrated Cyp1b1+/+ and Cyp1b1−/− mice and restored by treatment with 6β-OHT. Treatment with the androgen receptor antagonist flutamide reduced blood pressure and vascular hypertrophy in castrated Ang II-infused mice injected with 6β-OHT. Conclusions: 6β-OHT is required for the action of Ang II to increase vascular reactivity and cause endothelial dysfunction, hypertrophy, and increase in oxygen radical production. The effect of 6β-OHT in mediating Ang II-induced hypertension and associated hypertrophy is dependent on the androgen receptor. Therefore, CYP1B1 could serve as a novel target for the development of therapeutics to treat vascular changes in hypertensive males. [ABSTRACT FROM AUTHOR]

Background: Abnormal vascular reactivity and reduced expression of endothelial nitric oxide synthase (eNOS) gene are hallmark of salt-induced hypertension in rats. Although l -arginine is an established vasodilator, the mechanism by which it modulates vascular reactivity in salt-induced hypertension is not clearly understood. Objectives: This study was designed to investigate the mechanism by which oral l -arginine supplementation modulates vascular reactivity and eNOS gene expression in Sprague-Dawley rats fed a high-salt diet. Methods: Forty-eight weaned male Sprague-Dawley rats of weight range 90 to 110 g were randomly divided into 6 groups of 8 rats per group. Group I was fed normal rat chow ad libitum and served as the Normal Diet group. Group II was fed a diet that contained 8% NaCl. Groups III and IV took normal and high-salt diet, respectively, and then received oral l -arginine supplementation (100 mg/kg/day), while groups V and VI took normal and high-salt diet, respectively, and then were co-administered with both l -arginine and l -nitro-arginine methyl ester (L-NAME; 100 mg/kg/day and 40 mg/kg/day, respectively) orally. At the end of 12-week experimental period, the animals were sacrificed to assess vascular reactivity and gene expression level. Results: Our results show that high-salt diet significantly reduced (P <.05) endothelium-dependent relaxation response to acetylcholine and qualitatively reduced eNOS gene expression in the abdominal aorta of the rats. However, l -arginine supplementation improved the impaired endothelium-dependent relaxation and nitric oxide level while ameliorating the reduced eNOS gene expressions. Conclusion: This study suggests that oral supplementation of l -arginine enhances endothelial-dependent relaxation in rats fed a high-salt diet by ameliorating eNOS gene expression in the abdominal aorta of the rats. [ABSTRACT FROM AUTHOR]

Aim: Impairment of tissue responsiveness to exogenous and endogenous nitric oxide (NO•), known as NO• resistance, occurs in many cardiovascular disease states, prominently in diabetes and especially in the presence of marked hyperglycemia. In this study, we sought to determine in moderate and severe diabetes (i) whether NO• resistance also occurs in the myocardium, and (ii) whether the NO• redox sibling nitroxyl (HNO) circumvents this. Results: The spectrum of acute NO• effects (induced by diethylamine-NONOate), including vasodilation, and enhanced myocardial contraction and relaxation were impaired by moderately diabetic rats ([blood glucose] ∼20 mM). In contrast, acute HNO effects (induced by isopropylamine-NONOate) were preserved even in more severe diabetes ([blood glucose] >28 mM). Intriguingly, the positive inotropic effects of HNO were significantly enhanced in diabetic rat hearts. Further, progressive attenuation of soluble guanylyl cyclase (sGC) contribution to myocardial NO• responses occurred with increasing severity of diabetes. Nevertheless, activation of sGC by HNO remained intact in the myocardium. Innovation: Diabetes is associated with marked attenuation of vascular and myocardial effects of NO and NO donors, and this NO• resistance is circumvented by HNO, suggesting potential therapeutic utility for HNO donors in cardiovascular emergencies in diabetics. Conclusion: These results provide the first evidence that NO• resistance occurs in diabetic hearts, and that HNO largely circumvents this problem. Further, the positive inotropic and lusitropic effects of HNO are enhanced in a severely diabetic myocardium, a finding that warrants further mechanistic interrogation. The results support a potential role for therapeutic HNO administration in acute treatment of ischemia and/or heart failure in diabetics. [ABSTRACT FROM AUTHOR]

Aims The protein Scrib (Scribble 1) is known to control apico-basal polarity in epithelial cells. The role of polarity proteins in the vascular system remains poorly characterized; however, we previously reported that Scrib maintains the endothelial phenotype and directed migration. On this basis, we hypothesized that Scrib has anti-atherosclerotic functions. Methods and results Tamoxifen-induced Scrib-knockout mice were crossed with ApoE−/− knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine samples and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes. Conclusions By maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions. [ABSTRACT FROM AUTHOR]

This study aims to scrutinize the potential protective effect of diosmin and crocin against cardio-vascular complications attributed to metabolic syndrome (MS). For 16 weeks, the rats were given 10% fructose in water and 3% salt in diet to induce MS over a 16-week period. At week 7 and for 10 weeks, diosmin (50 mg/kg, PO) or crocin (50 mg/kg, PO) was administered daily. Non-invasive blood pressure (BP) was recorded in conscious animals. Thoracic aorta (macro vessels) and kidney (micro vessels) concentration-response curves for phenylephrine (PE) and acetylcholine (ACh) were analyzed. Electrocardiogram (ECG) parameters were recorded. Blood glucose level, serum insulin level, troponin T, advanced glycation end products (AGEs), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α) were measured. In addition, histological examination of aorta and heart tissues was performed. Diosmin and crocin alleviated cardio-vascular complications associated with MS. This is manifested in improvement of systolic and diastolic BP and ECG parameters. They ameliorated MS-induced exaggerated contractility to PE and improved the impaired dilatation to Ach in macro and micro vasculature. Diosmin and crocin reduced the elevated serum levels of insulin, AGEs, TNF-α, and MDA and reversed MS-induced structural changes of aorta and cardiac tissues. Diosmin and crocin offset the cardiac changes and vascular impairment associated with MS via attenuation of oxidative stress and suppression of inflammation. [ABSTRACT FROM AUTHOR]

To evaluate the effects of testosterone on endothelium-dependent vasodilation and oxidative stress in mesenteric resistance arteries. Spontaneously hypertensive rats (SHR), aged 8 to 10 weeks, were divided into four groups: intact (SHAM), intact treated with testosterone (TTO; 3 mg/kg/day) via subcutaneous route (s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO + ANA; 0.1 mg/kg/day, s.c.)] and intact treated with testosterone and finasteride [5 α-reductase enzyme inhibitor (TTO + FIN; 5 mg/kg/day, s.c.)] for four weeks. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L - 10 μmol/L) were obtained in mesenteric resistance arteries previously contracted with phenylephrine (PE, 3 μmol/L), before and after the use of selective inhibitors. Reactive oxygen species (ROS) levels were assessed in the vessels and the endothelium analyzed by scanning electron microscopy. TTO group showed a lower participation of nitric oxide (NO), increased oxidative stress, and participation of prostanoids and endothelium-dependent hyperpolarization (EDH), possibly to maintain the vasodilator response. Lower participation of NO and prostanoids, combined to an increased participation of EDH, were observed in the TTO + ANA group, in addition to higher levels of ROS and altered endothelial morphology. The vasodilation to ACh was impaired in TTO + FIN, along increased participation of NO, reduction of prostanoids, and greater EDH-dependent vasodilation. Testosterone contributes to endothelial vasodilation by enhancing EDH through an increased participation of epoxyeicosatrienoic acids. While the decrease in NO appears to involve the participation of dihydrotestosterone, 17 β-estradiol seems to stimulate the action of the NO pathway and prostanoids. [ABSTRACT FROM AUTHOR]

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk.

Pulmonary hypertension (PH) is a severe and multifactorial disease characterized by a progressive elevation of pulmonary arterial resistance and pressure due to remodeling, inflammation, oxidative stress, and vasoreactive alterations of pulmonary arteries (PAs). Currently, the etiology of these pathological features is not clearly understood and, therefore, no curative treatment is available. Since the 1990s, hydrogen sulfide (H2S) has been described as the third gasotransmitter with plethoric regulatory functions in cardiovascular tissues, especially in pulmonary circulation. Alteration in H2S biogenesis has been associated with the hallmarks of PH. H2S is also involved in pulmonary vascular cell homeostasis via the regulation of hypoxia response and mitochondrial bioenergetics, which are critical phenomena affected during the development of PH. In addition, H2S modulates ATP-sensitive K+ channel (KATP) activity, and is associated with PA relaxation. In vitro or in vivo H2S supplementation exerts antioxidative and anti-inflammatory properties, and reduces PA remodeling. Altogether, current findings suggest that H2S promotes protective effects against PH, and could be a relevant target for a new therapeutic strategy, using attractive H2S-releasing molecules. Thus, the present review discusses the involvement and dysregulation of H2S metabolism in pulmonary circulation pathophysiology.

The carry-over of zearalenone (ZEN) to the myocardium and its effects on coronary vascular reactivity in vivo have not been addressed in the literature to date. Therefore, the objective of this study was to verify the hypothesis that low ZEN doses (MABEL, NOAEL and LOAEL) administered per os to prepubertal gilts for 21 days affect the accumulation of ZEN, α-ZEL and β-ZEL in the myocardium and the reactivity of the porcine coronary arteries to vasoconstrictors: acetylcholine, potassium chloride and vasodilator sodium nitroprusside. The contractile response to acetylcholine in the presence of a cyclooxygenase (COX) inhibitor, indomethacin and / or an endothelial nitric oxide synthase (e-NOS) inhibitor, L-NAME was also studied. The results of this study indicate that the carry-over of ZEN and its metabolites to the myocardium is a highly individualized process that occurs even at very low mycotoxin concentrations. The concentrations of the accumulated ZEN metabolites are inversely proportional to each other due to biotransformation processes. The levels of vasoconstrictors, acetylcholine and potassium chloride, were examined in the left anterior descending branch of the porcine coronary artery after oral administration of ZEN. The LOAEL dose clearly decreased vasoconstriction in response to both potassium chloride and acetylcholine (P < 0.05 for all values) and increased vasodilation in the presence of sodium nitroprusside (P = 0.021). The NOAEL dose significantly increased vasoconstriction caused by acetylcholine (P < 0.04), whereas the MABEL dose did not cause significant changes in the vascular response. Unlike higher doses of ZEN, 5 μg/kg had no negative influence on the vascular system.

The aim of the present study is to investigate the effects of hypertension on the gap junctions between vascular smooth muscle cells (VSMCs) in the cerebral arteries (CAs) of spontaneously hypertensive rats (SHRs). The functions of gap junctions in the CAs of VSMCs in SHRs and control normotensive Wistar-Kyoto (WKY) rats were studied using whole-cell patch clamp recordings and pressure myography, and the expression levels of connexins were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blot analyses. Whole-cell patch clamp measurements revealed that the membrane capacitance and conductance of in situ VSMCs in the CAs were significantly greater in SHRs than in WKY rats, suggesting that gap junction coupling is enhanced between VSMCs in the CAs of SHRs. Application of the endothelium-independent vasoconstrictors KCl or phenylephrine (PE) stimulated a greater vasoconstriction in the CAs of SHRs than in those of WKY rats. The EC50 value of KCl was 24.9 mM (n = 14) and 36.9 mM (n=12) for SHRs and WKY rats, respectively. The EC50 value of PE was 0.9 µM (n = 7) and 2.2 µM (n = 7) for SHRs and WKY rats, respectively. Gap junction inhibitors 18β-glycyrrhetinic acid (18β-GA), niflumic acid (NFA), and 2-aminoethoxydiphenyl borate (2-APB) attenuated KCl-induced vasoconstriction in SHRs and WKY rats. The mRNA and protein expression levels of the gap junction protein connexin 45 (Cx45) were significantly higher in the CAs of SHRs than in those of WKY rats. Phosphorylated Cx43 protein expression was significantly higher in the CAs of SHRs than in those of WKY rats, despite the total Cx43 mRNA and protein expression levels in the cerebral artery (CA) exhibiting no significant difference between SHRs and WKY rats. Increases in the expression of Cx45 and phosphorylation of Cx43 may promote gap junction communication among VSMCs in the CAs of SHRs, which may enhance the contractile response of the CA to vasoconstrictors.

Background: The mechanisms underlying the perivascular adipose tissue (PVAT) dysfunction in obesity are closely related to inflammation and oxidative stress. The present study aimed to investigate the effects of aerobic exercise training on PVAT-induced endothelial dysfunction of thoracic aorta of obese mice.Methods: Male mice C57BL6/JUnib (6–7 weeks) were divided into: sedentary (c-SD), trained (c-TR), obese sedentary (o-SD), and obese trained (o-TR). Obesity was induced by 16 weeks of high-fat diet and exercise training of moderate intensity started after 8 weeks of protocol and was performed on a treadmill, 5 days/week, for more 8 weeks, 60 min per session. The vascular responsiveness was performed in thoracic aorta in the absence (PVAT−) or in the presence (PVAT+) of PVAT. We analyzed circulatory parameters, protein expression, vascular nitric oxide (NO) production, and reactive oxygen species (ROS) in PVAT.Results: The maximal responses to acetylcholine (ACh) were reduced in PVAT+ compared with PVAT− rings in the o-SD group, accompanied by an increase in circulating glucose, insulin, resistin, leptin, and TNF-α. Additionally, the protein expression of iNOS and generation of ROS were increased in PVAT and production of vascular NO was reduced in the o-SD group compared with c-SD. In the o-TR group, the relaxation response to ACh was completely restored and the circulatory TNF-α, iNOS protein expression, and ROS were normalized with increased expression of Mn-SOD in PVAT, resulting in enhanced vascular NO production.Conclusion: The PVAT-induced endothelial dysfunction in thoracic aorta of obese mice, associated with circulatory inflammation and oxidative stress. Aerobic exercise training upregulated the anti-oxidant expression and decreased PVAT oxidative stress with beneficial impact on endothelium-dependent relaxation.

The possibility of sex-related differences in mild traumatic brain injury (mTBI) severity and recovery remains a controversial subject. With some studies showing that female subjects suffer a longer period of symptom recovery, while others have failed to demonstrate differences. In this study, we explored the sex-related effects of mTBI on self-reported symptoms and transcranial Doppler ultrasound (TCD) measured features in an adolescent population. Fifty-eight subjects were assessed—at different points post-injury—after suffering an mTBI. Subjects answered a series of symptom questions before the velocity from the middle cerebral artery was measured. Subjects participated in breath-holding challenges to evaluate cerebrovascular reactivity. The Pulsatility Index (PI), the ratio of the first peaks (P2R), and the Breath-Hold Index (BHI), were computed. Linear mixed effects models were developed to explore the interactions between measured features, sex, and time since injury while accounting for within subject variation. Over the first 10 days post-injury, the female group had significant interactions between sex and time since injury that was not present in the TCD features. This is the first study to compare sex-related differences in self-reported symptoms and TCD measurements in adolescents suffering an mTBI. It illustrates the pitfalls clinicians face when relying on subjective measures alone during diagnosis and tracking of mTBI patients. In addition, it highlights the need for more focused research on sex-related differences in concussion pathophysiology.

Experimental studies show that the unsaturated high-fat diet-induced obesity promotes vascular alterations characterized by improving the endothelial L-arginine/Nitric Oxide (NO) pathway. Leptin seems to be involved in this process, promoting vasodilation via increasing NO bioavailability. The aim of this study was to test the hypothesis that unsaturated high-fat diet-induced obesity does not generate endothelial dysfunction via increasing the vascular leptin/Akt/eNOS signaling. Thirty-day-old male Wistar rats were randomized into two groups: control (C) and obese (Ob). Group C was fed a standard diet, while group Ob was fed an unsaturated high-fat diet for 27 weeks. Adiposity, hormonal and biochemical parameters, and systolic blood pressure were observed. Concentration response curves were performed for leptin or acetylcholine in the presence or absence of Akt and NOS inhibitor. Our results showed that an unsaturated high-fat diet promoted a greater feed efficiency (FE), elevation of body weight and body fat (BF), and an adiposity index, characterizing a model of obesity. However, comorbidities frequently associated with experimental obesity were not visualized, such as glucose intolerance, dyslipidemia and hypertension. The evaluation of the endothelium-dependent relaxation with acetylcholine showed no differences between the C and Ob rats. After NOS inhibition, the response was completely abolished in the Ob group, but not in the C group. Furthermore, Akt inhibition completely blunted vascular relaxation in the C group, but not in the Ob group, which was more sensitive to leptin-induced vascular relaxation. L-NAME incubation abolished the relaxation in both groups at the same level. Although Akt inhibitor pre-incubation reduced the leptin response, group C was more sensitive to its effect. In conclusion, the high-unsaturated fat diet-induced obesity improved the vascular reactivity to leptin and does not generate endothelial dysfunction, possibly by the increase in the vascular sensitivity to leptin and increasing NO bioavailability. Moreover, our results suggest that the increase in NO production occurs through the increase in NOS activation by leptin and is partially mediated by the Akt pathway.

Objectives: Quantitative regional cerebral perfusion (rCBF) measurements using [ 15 O]H 2 O 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 [ 15 O]H 2 O PET measurements in patients not subsequently undergoing surgery., Methods: We identified 32 eligible patients who underwent [ 15 O]H 2 O 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 (rCBF base ) and after (rCBF acz ) 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 rCBF acz (AUC:0.82) compared to CVR (AUC:0.72) and rCBF base (AUC:0.77). ROC AUC, optimal thresholds (and corresponding sensitivity/specificity/accuracy) for rCBF acz 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 rCBF acz below cut-off (p=0.007). In multivariate analysis rCBF acz remained a significant predictor when correcting for age., Conclusion: Quantitative rCBF measurements after ACZ challenge with [ 15 O]H 2 O PET provided high prognostic value for future cerebrovascular events., Competing Interests: Declaration of Competing Interest None of the authors declare any conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants frequently detected in drinking water worldwide. Reports linking PFAS exposure to cardiovascular disease have increased significantly in recent years. Furthermore, women appear to be more susceptible to the adverse effects of PFAS. However, the potential role of ovaries in the increased vulnerability of females to PFAS-related health effects remains unknown. In this study, we investigated the impact of perfluorooctane sulfonate (PFOS), a prominent PFAS, on the cardiovascular function in female rats with intact ovaries and ovariectomized (OVX) females. Bilateral OVX or sham surgeries were performed in 8-week-old female SD rats. Following recovery from surgeries, the rats were given drinking water containing 50 μg/mL of PFOS for 3 weeks. Control groups received PFOS-free water. PFOS exposure significantly reduced body weight but increased blood pressure similarly in both intact and OVX rats. Echocardiography analysis revealed that PFOS exposure decreased cardiac output, end-systolic volume, and end-diastolic volume in intact but not OVX rats. Vascular function studies demonstrated that PFOS equally reduced endothelium-dependent and -independent relaxation responses in intact and OVX rats. The endothelium-independent contractile responses were more pronounced in both intact and OVX rats. eNOS protein levels were similarly decreased in both intact and OVX rats. In conclusion, PFOS affects cardiac function through hormone-dependent mechanisms, while vascular function is impaired independent of ovarian status, indicating an intricate interplay between PFOS exposure, ovarian status, and cardiovascular function., Competing Interests: Declarations Conflict of interest Authors declare no conflict of interest.

Receptor tyrosine kinases have been implicated in various vascular remodeling processes and cardiovascular disease. However, their role in the regulation of vascular tone is poorly understood. Herein, we evaluate the contribution of c-Kit signaling to vasoactive responses. The vascular reactivity of mesenteric arteries was assessed under isobaric conditions in c-Kit deficient (KitW/W−v) and littermate control mice (Kit+/+) using pressure myography. Protein levels of soluble guanylyl cyclase beta 1 (sGCβ1) were quantified by Western blot. Mean arterial pressure was measured after high salt (8% NaCl) diet treatment using the tail-cuff method. Smooth muscle cells (SMCs) from c-Kit deficient mice showed a 5-fold downregulation of sGCβ1 compared to controls. Endothelium-dependent relaxation of mesenteric arteries demonstrated a predominance of prostanoid vs. nitric oxide (NO) signaling in both animal groups. The dependence on prostanoid-induced dilation was higher in c-Kit mutant mice than in controls, as indicated by a significant impairment in vasorelaxation with indomethacin with respect to the latter. Endothelium-independent relaxation showed significant dysfunction of NO signaling in c-Kit deficient SMCs compared to controls. Mesenteric artery dilation was rescued by addition of a cGMP analog, but not with a NO donor, indicating a deficiency in cGMP production in c-Kit deficient SMCs. Finally, c-Kit deficient mice developed higher blood pressure on an 8% NaCl diet compared to their control littermates. c-Kit deficiency inhibits NO signaling in SMCs. The existence of this c-Kit/sGC signaling axis may be relevant for vascular reactivity and remodeling. • Deficiency in c-Kit leads to impaired nitric oxide signaling in smooth muscle cells. • c-Kit plays a role in nitric oxide-mediated vascular relaxation. • c-Kit/sGC signaling axis contributes to vascular relaxation. [ABSTRACT FROM AUTHOR]

Hypoxic pulmonary vasoconstriction (HPV) is a protective mechanism maintaining blood oxygenation by redirecting blood flow from poorly ventilated to well‐ventilated areas in the lung. Such a beneficial effect is blunted by antihypertensive treatment with dihydropyridine calcium channel inhibitors. The aim of the present study was to evaluate the effect of urapidil, an antihypertensive agent acting as an α1 adrenergic antagonist and a partial 5‐HT1A agonist, on HPV in porcine proximal and distal pulmonary artery rings, and to characterize underlying mechanisms. Rings from proximal and distal porcine pulmonary artery were suspended in organ chambers and aerated with a 95% O2 + 5% CO2 gas mixture. HPV was induced by changing the gas to a 95% N2 + 5% CO2 mixture following a low level of pre‐contraction with U46619. Hypoxia induced a contractile response in both proximal and distal pulmonary artery rings. This effect is observed in the presence of a functional endothelium and is inhibited by a soluble guanylyl cyclase inhibitor (ODQ), a NO scavenger (carboxy‐PTIO), and by catalase in proximal pulmonary artery rings. The endothelium‐dependent HPV is prevented by nicardipine and clevidipine but remained unaffected by urapidil in both proximal and distal pulmonary artery rings. These findings indicate that urapidil, in contrast to nicardipine and clevidipine, preserves the hypoxia‐triggered vasoconstriction in isolated pulmonary arteries. They further indicate the involvement of the NO‐guanylyl cyclase pathway and H2O2 in HPV. Further research is warranted to determine the potential clinical relevance of the preserved hypoxia‐induced pulmonary vasoconstriction by urapidil. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is often complicated by difficult-to-control hypertension, in part due to chronic overactivation of the sympathetic nervous system (SNS). CKD patients also exhibit a greater increase in arterial blood pressure for a given increase in sympathetic nerve activation, suggesting an augmented vasoconstrictive response to SNS activation (i.e., neurovascular transduction). One potential mechanism of increased sympathetic neurovascular transduction is heightened sensitivity of the vascular α1-adrenergic receptors (α1ARs), the major effectors of vasoconstriction in response to norepinephrine release at the sympathetic nerve terminals. Therefore, we hypothesized that patients with CKD have increased vascular α1AR sensitivity. We studied 32 patients with CKD stages III and IV (age 59.9 ± 1.3 yr) and 19 age-matched controls (CON, age 63.2 ± 1.6 yr). Using a linear variable differential transformer (LVDT), we measured change in venoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine (PE) administered sequentially into a dorsal hand vein. Individual semilogarithmic PE dose-response curves were constructed for each participant to determine the PE dose at which 50% of maximum venoconstriction occurred (ED50), reflecting α1AR sensitivity. In support of our hypothesis, CKD patients had a lower PE ED50 than CON (CKD = 2.23 ± 0.11 vs. CON = 2.63 ± 0.20, P = 0.023), demonstrating increased vascular α1AR sensitivity. Additionally, CKD patients had a greater venoconstrictive capacity to PE than CON (P = 0.015). Augmented α1AR sensitivity may contribute mechanistically to enhanced neurovascular transduction in CKD and may explain, in part, the greater blood pressure reactivity exhibited in these patients. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying the perivascular adipose tissue (PVAT) dysfunction in obesity are closely related to inflammation and oxidative stress. The present study aimed to investigate the effects of aerobic exercise training on PVAT-induced endothelial dysfunction of thoracic aorta of obese mice. Methods: Male mice C57BL6/JUnib (6–7 weeks) were divided into: sedentary (c-SD), trained (c-TR), obese sedentary (o-SD), and obese trained (o-TR). Obesity was induced by 16 weeks of high-fat diet and exercise training of moderate intensity started after 8 weeks of protocol and was performed on a treadmill, 5 days/week, for more 8 weeks, 60 min per session. The vascular responsiveness was performed in thoracic aorta in the absence (PVAT−) or in the presence (PVAT+) of PVAT. We analyzed circulatory parameters, protein expression, vascular nitric oxide (NO) production, and reactive oxygen species (ROS) in PVAT. Results: The maximal responses to acetylcholine (ACh) were reduced in PVAT+ compared with PVAT− rings in the o-SD group, accompanied by an increase in circulating glucose, insulin, resistin, leptin, and TNF-α. Additionally, the protein expression of iNOS and generation of ROS were increased in PVAT and production of vascular NO was reduced in the o-SD group compared with c-SD. In the o-TR group, the relaxation response to ACh was completely restored and the circulatory TNF-α, iNOS protein expression, and ROS were normalized with increased expression of Mn-SOD in PVAT, resulting in enhanced vascular NO production. Conclusion: The PVAT-induced endothelial dysfunction in thoracic aorta of obese mice, associated with circulatory inflammation and oxidative stress. Aerobic exercise training upregulated the anti-oxidant expression and decreased PVAT oxidative stress with beneficial impact on endothelium-dependent relaxation. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction and vascular reactivity defects secondary to metabolic and immunological disorders carry risk of serious cardiovascular complications. Here, the effects of the phosphodiesterase (PDE) inhibitors vardenafil and cilostazol were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced endothelial dysfunction and vascular reactivity defects. After setting of RA/DM-co-morbidity model, rats were divided into a normal control group, an RA/DM-co-morbidity group, and two treatment groups receiving oral vardenafil (10 mg/kg/day) and cilostazol (30 mg/kg/day) for 21 days after RA/DM-co-morbidity induction. Aorta was isolated for biochemical estimations of the pro-inflammatory vasoconstrictor molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy sensor adenosine-5′-monophosphate-activated protein kinase (AMPK), and the vasodilator anti-inflammatory molecule vasoactive intestinal peptide (VIP) using enzyme-linked immunosorbent assay (ELISA) and western blot analysis. Immunohistochemical estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed coupled with histopathological examination using routine hematoxylin and eosin (H&E) and special Masson trichrome staining. The in vitro study was conducted using aortic strips where cumulative concentration response curves were done for the endothelium-dependent relaxing factor acetylcholine and the endothelium-independent relaxing factor sodium nitroprusside after submaximal contraction with phenylephrine. Vardenafil and cilostazol significantly improved endothelial integrity biomarkers in vivo supported with histopathological findings in addition to improved vasorelaxation in vitro. Apart from their known PDE inhibition, up-regulation of vascular AMPK and eNOS coupled with down-regulation of Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 may explain vardenafil and cilostazol protective effect against RA/DM-co-morbidity-induced endothelial dysfunction and vascular reactivity defects. [ABSTRACT FROM AUTHOR]

Previous studies have shown that vascular reactivity evaluated in female rat aorta to norepinephrine did not present the same response at all periods of their estrous cycle. During proestrus, the contractile response shows lower values. It was also reported that vascular reactivity had a close relationship with prostaglandins activity. In this study, we studied the response to norepinephrine in rat aorta rings treated with indomethacin. Indomethacin is a well-known inhibitor of prostaglandin synthesis. At low concentrations, the effect of indomethacin was not significant, and vascular reactivity response to norepinephrine was similar to those aortic rings from the control rats (without indomethacin). However, at high concentrations of norepinephrine, a marked difference was observed. The inhibitory action of indomethacin on the synthesis of prostaglandins was effectively reflected in a lower release of prostaglandins. In this way, our results confirm previous findings and indicate that indomethacin increases the constrictor response to norepinephrine, avoiding the vasodilatory effect of prostaglandins. [ABSTRACT FROM AUTHOR]

Purpose: Literature reports contradicting results on the response of brain tumors to vascular stimuli measured in T2*-weighted MRI. Here, we analyzed the potential dependency of the MRI-response to (hypercapnic) hyperoxia on the order of the gas administration. Methods: T2* values were quantified at 3 Tesla in eight consenting patients at rest and during inhalation of hyperoxic/hypercapnic gas mixtures. Patients were randomly divided into two groups undergoing different gas administration protocols (group A: medical air-pure oxygen–carbogen; group B: medical air–carbogen-pure oxygen). Mann-Whitney U test and Wilcoxon signed rank test have been used to proof differences in T2* regarding respiratory challenge or different groups, respectively. Results: T2* values at rest for gray and white matter were 50.3 ± 2.6 ms and 46.1 ± 2.0 ms, respectively, and slightly increased during challenge. In tumor areas, T2* at rest were: necrosis = 74.1 ± 10.1 ms; edema = 60.3 ± 17.6 ms; contrast-enhancing lesions = 48.6 ± 20.7 ms; and solid T2-hyperintense lesions = 45.0 ± 3.0 ms. Contrast-enhancing lesions strongly responded to oxygen (+ 20.7%) regardless on the gas protocol (p = 0.482). However, the response to carbogen significantly depended on the order of gas administration (group A, + 18.6%; group B, − 6.4%, p = 0.042). In edemas, a different trend between group was found when breathing oxygen (group A, − 9.9%; group B, + 19.5%, p = 0.057). Conclusion: Preliminary results show a dependency of the T2* response of contrast-enhancing brain tumor lesions on the order of the gas administration. The gas administration protocol is an important factor in the interpretation of the T2*-response in areas of abnormal vascular growth. [ABSTRACT FROM AUTHOR]

• We discovered a relationship between vascular (via breath-hold) and functional response in healthy subjects and subjects who underwent pre-surgical planning fMRI. • This "vaso-task dependency" can be utilized to estimate the effects of neurovascular uncoupling. • Neurovascular uncoupling can be overcome partially by using the vaso-task dependency to model vasoreactivity affected by brain tumors. Preoperative functional MRI (fMRI) is limited by a muted BOLD response caused by abnormal vasoreactivity and resultant neurovascular uncoupling adjacent to malignant brain tumors. We propose to overcome this limitation and more accurately identify eloquent areas adjacent to brain tumors by independently assessing vasoreactivity using breath-holding and incorporating these data into the fMRI analysis. Local vasoreactivity using a breath-holding paradigm with the same timing as the functional motor and language tasks was determined in 16 patients (9 glioblastomas, 1 anaplastic astrocytoma, 5 low grade astrocytomas, and 1 metastasis) and 6 healthy control subjects. We derived an fMRI model based on an observed vaso-task response dependency that takes into account the altered hemodynamics adjacent to brain tumors. In both healthy controls and brain tumor subjects, we found a statistical dependency between breath-hold and task BOLD response. In tumor subjects, activation maps that take into account this vaso-task dependency demonstrated clinically meaningful areas of activation that were not seen using the task-only analysis in about half of the cases studied. This included localization of language areas adjacent to brain tumors. The present preliminary results demonstrate that neurovascular uncoupling known to affect the accuracy of BOLD fMRI adjacent to brain tumors may be, at least partially, overcome by incorporating an observed vaso-task dependency in the BOLD signal analysis. [ABSTRACT FROM AUTHOR]

The possibility of sex-related differences in mild traumatic brain injury (mTBI) severity and recovery remains a controversial subject. With some studies showing that female subjects suffer a longer period of symptom recovery, while others have failed to demonstrate differences. In this study, we explored the sex-related effects of mTBI on self-reported symptoms and transcranial Doppler ultrasound (TCD) measured features in an adolescent population. Fifty-eight subjects were assessed—at different points post-injury—after suffering an mTBI. Subjects answered a series of symptom questions before the velocity from the middle cerebral artery was measured. Subjects participated in breath-holding challenges to evaluate cerebrovascular reactivity. The Pulsatility Index (PI), the ratio of the first peaks (P2R), and the Breath-Hold Index (BHI), were computed. Linear mixed effects models were developed to explore the interactions between measured features, sex, and time since injury while accounting for within subject variation. Over the first 10 days post-injury, the female group had significant interactions between sex and time since injury that was not present in the TCD features. This is the first study to compare sex-related differences in self-reported symptoms and TCD measurements in adolescents suffering an mTBI. It illustrates the pitfalls clinicians face when relying on subjective measures alone during diagnosis and tracking of mTBI patients. In addition, it highlights the need for more focused research on sex-related differences in concussion pathophysiology. [ABSTRACT FROM AUTHOR]

Prosopis species is a medicinal plant, well-known for its beneficial effects in treating various smooth muscles disorders, and its phytochemical analysis revealed the presence of different bioactive compounds in different parts of the plant, most of which show a great role in reducing cardiovascular risks. In the present study, the cardiovascular effect of Prosopis farcta Root Extract (PFRE) was investigated in vitro for possible mechanisms of the extract effect in the vascular reactivity of isolated goat coronary artery (CA) using Organ bath and PoweLab Data Acquisition system. The results of the recording and analyzing of the effect of the PFRE in isolated CA, showed the negative inotropic activity of the extract in CA rings with intact-endothelium, while in CA ring with hyperglycemic-induced endothelium dysfunction the extract tended to vasodilate the CA ring nonsignificantly, and the extract induced dose-dependent vasodilation in CA rings pre-constricted with high concentration of (30 mM)KCl and showed no effects on contractions induced by (1X10-3-1X10-5) Phenylephrine PE, which is an indicator for its blockade activity on L-type voltage-dependent Ca+2 channel and non-interfering of the extract with the receptor-operated Ca+2 channel. The mechanical recording of the CA ring activities, revealed different potassium (K+) channels including selective calcium-activated potassium channel, ATP-sensitive potassium channel, and different endothelium-derived relaxing factors (EDRF) including nitric oxide and Prostacyclin (PGI2) seems to have no role in the relaxation effects of the extract, while the endothelium derivedhyperpolarizing factor (EDHF); epoxy eicosatrienoic acid (EET) showed significant participation in the vasodilation effects of the extract. On the other hand, the extract tended to relax the CA rings through its antagonizing of Ca+2, reducing and inhibiting Ca+2 influx and release from internal stores and interfering with the voltage-operated Ca+2 channels through its alkaloid and flavonoid active compounds which suggested to be the most predicted mechanisms for the maintenance of vasodilating tone and coronary circulation of the PFRE in coronary artery. [ABSTRACT FROM AUTHOR]

Key points: A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries.In the present study, we report that high altitude‐induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance.Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude‐related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis.The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. A high altitude (HA) stay is associated with an increase in sublingual capillary total vessel density (TVD), suggesting microvascular recruitment. We hypothesized that microvascular recruitment occurs independent of cardiac output changes, that it relies on haemodynamic changes within the microcirculation as opposed to structural changes and that microcirculatory function is related to individual performance at HA. In 41 healthy subjects, sublingual handheld vital microscopy and echocardiography were performed at sea level (SL), as well as at 6022 m (C2) and 7042 m (C3), during ascent to 7126 m within 21 days. Sublingual topical nitroglycerin was applied to measure microvascular reactivity and maximum recruitable TVD (TVDNG). HA exposure decreased resting cardiac output, whereas TVD (mean ± SD) increased from 18.81 ± 3.92 to 20.92 ± 3.66 and 21.25 ± 2.27 mm mm−2 (P < 0.01). The difference between TVD and TVDNG was 2.28 ± 4.59 mm mm−2 at SL (P < 0.01) but remained undetectable at HA. Maximal TVDNG was observed at C3. Those who reached the summit (n = 15) demonstrated higher TVD at SL (P < 0.01), comparable to TVDNG in non‐summiters (n = 21) at SL and in both groups at C2. Recruitment of sublingual capillary TVD to increase microcirculatory oxygen extraction capacity at HA was found to be an intrinsic mechanism of the microcirculation independent of cardiac output changes. Microvascular reactivity to topical nitroglycerin demonstrated that HA‐related capillary recruitment is a functional response as opposed to a structural change. The performance of the vascular microcirculation needed to reach the summit was found to be associated with a higher TVD at SL and the ability to further increase TVDNG upon ascent to extreme altitude. Key points: A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries.In the present study, we report that high altitude‐induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance.Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude‐related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis.The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. [ABSTRACT FROM AUTHOR]

Background/Aims: Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators. Methods: Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points. In addition, sGC expression was detected by immunohistochemistry. Results: At 1 day after injury, acidified sodium nitrite-induced relaxation was attenuated in the injured artery, whereas BAY 60-2770-induced relaxation was augmented. Similar attenuation of response to acidified sodium nitrite was seen at 7 and 14 days after injury. On the other hand, the augmentation of response to BAY 60-2770 disappeared at 7 and 14 days after injury. At 1 day after injury, the immunohistochemical expression pattern of sGC in the smooth muscle layer of the injured artery was not different from that of the uninjured artery. However, in the injured artery, the intensity of sGC staining was weak at 7 and 14 days after injury. Conclusion: Balloon injury alters vascular responsiveness to cGMP generators, which seems to be associated with the form and/or expression of sGC. [ABSTRACT FROM AUTHOR]

Background We sought to determine the effects of unilateral lower-limb external pneumatic compression (EPC) on bilateral lower-limb vascular reactivity and skin blood flow. Methods Thirty-two participants completed this two-aim study. In AIM1 (n = 18, age: 25.5 ± 4.7 years; BMI: 25.6 ± 3.5 kg/m²), bilateral femoral artery blood flow and reactivity (flow mediated dilation [FMD]) measurements were performed via ultrasonography at baseline (PRE) and immediately following 30-min of unilateral EPC treatment (POST). AIM2 (n = 14, age: 25.9 ± 4.5; BMI: 27.2 ± 2.7 kg/m²) involved 30-min unilateral EPC (n = 7) or sham (n = 7) treatment with thermographic bilateral lower-limb mean skin temperature (MST) measurements at baseline, 15-min of treatment (T15) and 0, 30 and 60-min (R0, R30, R60) following treatment. Results Comparative data herein are presented as mean ± 95% confidence interval. AIM1: No significant effects on total reactive hyperemia blood flow were observed for the treated (i.e., compressed) or untreated (i.e., non-compressed) leg. A significant effect of time, but no time*leg interaction, was observed for relative FMD indicating higher reactivity bilaterally with unilateral EPC treatment (FMD: +0.41 ± 0.09% across both legs; p < 0.05). AIM2: Unilateral EPC treatment was associated with significant increases in whole-leg MST from baseline during (T15: +0.63 ± 0.56 °C in the visible untreated/contralateral leg, p < 0.025) and immediately following treatment (i.e., R0) in both treated (+1.53 ± 0.59 °C) and untreated (+0.60 ± 0.45 °C) legs (p < 0.0125). Across both legs, MST remained elevated with EPC at 30-min post-treatment (+0.60 ± 0.45 °C; p < 0.0167) but not at 60-min post (+0.27 ± 0.46 °C; p = 0.165). Sham treatment was associated with a significant increase in the treated leg immediately post-treatment (+1.12 ± 0.31 °C; p < 0.0167), but not in the untreated leg (−0.27 ± 0.12 °C). MST in neither the treated or untreated leg were increased relative to baseline at R30 or R60 (p > 0.05). Finally, during treatment and at all post-treatment time points (i.e., R0, R30 and R60), independent of treatment group (EPC vs. sham), there was a significant effect of region. The maximum increase in MST was observed at the R0 time point and was significantly (p < 0.05) larger in the thigh region (+1.02 ± 0.31 °C) than the lower-leg (+0.47 ± 0.29 °C) region. However, similar rates of MST decline from R0 in the thigh and lower leg regions were observed at the R30 and R60 time points. Discussion Unilateral EPC may be an effective intervention for increasing skin blood flow and/or peripheral conduit vascular reactivity in the contralateral limb. While EPC was effective in increasing whole-leg MST bilaterally, there appeared to be a more robust response in the thigh compared to the lower-leg. Thus, proximity along the leg may be an important consideration in prospective treatment strategies. [ABSTRACT FROM AUTHOR]

Pre‐eclampsia and hypertensive disorders of pregnancy are frequently associated with foeto‐placental growth restriction, and that may be triggered by angiogenic imbalance and endothelial dysfunction. Impaired nitric oxide (NO) bioavailability seems to be involved in these pathophysiological changes observed in hypertensive pregnancy. Pravastatin has shown efficacy and to be safe during hypertension in pregnancy. However, NO involvement in pravastatin effects during maternal hypertension and foeto‐placental development is unclear. Therefore, we aimed to examine pravastatin effects on placental NO formation, endothelium‐dependent vasodilation, systolic blood pressure and foeto‐placental development in hypertensive pregnant rats. Biochemical determinants of angiogenesis and oxidative stress were also assessed. Pregnant rats were distributed into four groups: normal pregnancy (Norm‐Preg), pregnancy+pravastatin (Preg‐Prava), hypertensive pregnancy (HTN‐Preg) and hypertensive pregnancy+pravastatin (HTN‐Preg+Prava). Our results showed that pravastatin treatment blunts hypertension and foeto‐placental growth restriction. Also, increases in placental NO levels were found in the HTN‐Preg+Prava group. Pravastatin prevents impaired endothelium‐dependent acetylcholine‐induced vasodilation, exacerbated contractile response to phenylephrine and increases in oxidative stress in the HTN‐Preg+Prava group. Increased soluble fms‐like tyrosine kinase‐1‐to‐placental growth factor (sFlt‐1/PlGF) ratio is reversed by pravastatin treatment in the HTN‐Preg+Prava group. We conclude that NO formation and endothelium‐dependent vasodilation underlie pleiotropic effects associated with pravastatin treatment against hypertension in pregnancy, intrauterine growth restriction, vascular dysfunction and angiogenic imbalance. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion (I/R) injury involves damage to the microvessel structure (eg, increased permeability) and function (blunted vasomodulation). While microstructural damage can be detected with dynamic contrast-enhanced (DCE) MRI, there is no diagnostic to detect deficits in microvascular function.Purpose: To apply a novel MRI method for evaluating dynamic vasomodulation to assess microvascular dysfunction in skeletal muscle following I/R injury.Study Type: Prospective, longitudinal.Animal Model: Twenty-three healthy male adult Sprague-Dawley rats.Field Strength/sequence: Dynamic T1 fast field echo imaging at 3.0T with preinjection T1 mapping.Assessment: Injury in the left hindlimb was induced using a 3-hour I/R procedure. Longitudinal MRI scanning was performed up to 74 days, with animals completing assessment at different intervals for histological and laser Doppler perfusion validation. Pharmacokinetic parameters Ktrans and ve were determined following i.v. injection of gadovist (0.1 mmol/kg). Vasomodulatory response was probed on gadofosveset (0.3 mmol/kg) using hypercapnic gases delivered through a controlled gas-mixing circuit to induce vasoconstriction and vasodilation in ventilated rats. Heart rate and blood oxygen saturation were monitored.Statistical Tests: Two-way analysis of variance with Tukey-Kramer post-hoc analysis was used to determine significant changes in vasomodulatory response, Ktrans , and ve .Results: This new MRI technique revealed impaired vasomodulation in the injured hindlimb. Vasoconstriction was maintained, but vasodilation was blunted up to 21 days postinjury (P < 0.05). However, DCE-MRI measured Ktrans and ve were significantly (P < 0.05) different from baseline only during acute inflammation (Day 3), with severe inflammation noted on histology.Data Conclusion: While conventional DCE-MRI shows normalization after the acute phase, our new approach reveals sustained functional impairment in muscle microvasculature following I/R injury, with compromised response in vasomotor tone present for at least 21 days.Level Of Evidence: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1174-1185. [ABSTRACT FROM AUTHOR]

Experimental studies show that the unsaturated high-fat diet-induced obesity promotes vascular alterations characterized by improving the endothelial L-arginine/Nitric Oxide (NO) pathway. Leptin seems to be involved in this process, promoting vasodilation via increasing NO bioavailability. The aim of this study was to test the hypothesis that unsaturated high-fat diet-induced obesity does not generate endothelial dysfunction via increasing the vascular leptin/Akt/eNOS signaling. Thirty-day-old male Wistar rats were randomized into two groups: control (C) and obese (Ob). Group C was fed a standard diet, while group Ob was fed an unsaturated high-fat diet for 27 weeks. Adiposity, hormonal and biochemical parameters, and systolic blood pressure were observed. Concentration response curves were performed for leptin or acetylcholine in the presence or absence of Akt and NOS inhibitor. Our results showed that an unsaturated high-fat diet promoted a greater feed efficiency (FE), elevation of body weight and body fat (BF), and an adiposity index, characterizing a model of obesity. However, comorbidities frequently associated with experimental obesity were not visualized, such as glucose intolerance, dyslipidemia and hypertension. The evaluation of the endothelium-dependent relaxation with acetylcholine showed no differences between the C and Ob rats. After NOS inhibition, the response was completely abolished in the Ob group, but not in the C group. Furthermore, Akt inhibition completely blunted vascular relaxation in the C group, but not in the Ob group, which was more sensitive to leptin-induced vascular relaxation. L-NAME incubation abolished the relaxation in both groups at the same level. Although Akt inhibitor pre-incubation reduced the leptin response, group C was more sensitive to its effect. In conclusion, the high-unsaturated fat diet-induced obesity improved the vascular reactivity to leptin and does not generate endothelial dysfunction, possibly by the increase in the vascular sensitivity to leptin and increasing NO bioavailability. Moreover, our results suggest that the increase in NO production occurs through the increase in NOS activation by leptin and is partially mediated by the Akt pathway. [ABSTRACT FROM AUTHOR]

Clinical studies have shown that obesity negatively impacts large arteries' function. We reported that rats exposed to maternal separation (MatSep), a model of early life stress, display enhanced angiotensin II (ANG II)-induced vasoconstriction in aortic rings cleaned of perivascular adipose tissue (PVAT) under normal diet (ND) conditions. We hypothesized that exposure to MatSep promotes a greater loss of PVAT-mediated protective effects on vascular function and loss of blood pressure (BP) rhythm in rats fed a high-fat diet (HFD) when compared with controls. MatSep was performed in male Wistar-Kyoto rats from days 2 to 14 of life. Normally reared littermates served as controls. On ND, aortic rings from MatSep rats with PVAT removed showed increased ANG II-mediated vasoconstriction versus controls; however, rings from MatSep rats with intact PVAT displayed blunted constriction. This effect was exacerbated by an HFD in both groups; however, the anticontractile effect of PVAT was greater in MatSep rats. Acetylcholine-induced relaxation was similar in MatSep and control rats fed an ND, regardless of the presence of PVAT. HFD impaired aortic relaxation in rings without PVAT from MatSep rats, whereas the presence of PVAT improved relaxation in both groups. On an HFD, immunolocalization of vascular smooth muscle-derived ANG-(1-7) and PVAT-derived adiponectin abundances were increased in MatSep. In rats fed an HFD, 24-h BP and BP rhythms were similar between groups. In summary, MatSep enhanced the ability of PVAT to blunt the heightened ANG II-induced vasoconstriction and endothelial dysfunction in rats fed an HFD. This protective effect may be mediated via the upregulation of vasoprotective factors within the adipovascular axis. [ABSTRACT FROM AUTHOR]

Background/Aims: Reduction of renal blood flow (RBF) is commonly thought to be a causative factor of renal dysfunction in congestive heart failure (CHF), but the exact mechanism of the renal hypoperfusion is not clear. Apart from the activation of neurohormonal systems controlling intrarenal vascular tone, the cause might be altered reactivity of the renal vasculature to endogenous vasoactive agents. Methods: To evaluate the role of this mechanism, we assessed by an ultrasonic transient-time flow probe maximum RBF responses to renal artery infusion of angiotensin II (ANG II), norepinephrine (NE) and acetylcholine (Ach) in healthy male rats and animals with compensated and decompensated CHF. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF) in Hannover Sprague-Dawley rats. Results: Maximum responses in RBF to ANG II were similar in rats studied five weeks (compensated phase) and 20 weeks (decompensated phase) after ACF creation when compared to sham-operated rats. On the other hand, NE elicited larger maximum decreases in RBF in rats with CHF (five and 20 weeks post-ACF) than in sham-operated controls. We observed greater maximum vasodilatory responses to Ach only in rats with a compensated stage of CHF (five weeks post-ACF). Conclusion: Greater renal vasoconstrictor responsiveness to ANG II or reduced renal vasodilatation in response to Ach do not play a decisive role in the development of renal dysfunction in ACF rats with compensated and decompensated CHF. On the other hand, exaggerated renal vascular responsiveness to NE may be here a contributing causative factor, active in either CHF phase. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.

Hypercholesterolemia is an important risk factor for development of cardiovascular disturbances, such as atherosclerosis, and its treatment remains challenging in modern medicine. Cilostazol is a selective inhibitor of phosphodiesterase 3 clinically prescribed for intermittent claudication treatment. Due to its pleiotropic properties, such as lipid lowering, anti-inflammatory, and antioxidant effects, the therapeutic repurposing of cilostazol has become a strategic approach for atherosclerosis treatment. This study aimed to investigate the effects of subacute administration of cilostazol on the aortas of hypercholesterolemic rats, focusing on the signaling pathways involved in these actions. A murine model of hypercholesterolemia was employed to mimic the early stages of atherosclerosis development. Vascular reactivity assays were performed on thoracic aorta rings to assess the vascular response, as well as the non-invasive blood pressure was evaluated by plethysmography method. Pro-inflammatory markers and malondialdehyde (MDA) levels were measured to investigate the anti-inflammatory and antioxidant effects of cilostazol. Western Blot analysis was performed in aortas homogenates to evaluate the role of cilostazol on PLC-γ/PKC-α/p38-MAPK/IκB-α/NF-кB and PKA/eNOS/PKG pathways. The hypercholesterolemic diet induced the production of pro-inflammatory mediators such as TNF-α, TXB 2 , VCAM, and worsened vascular function, marked by increased contractile response, decreased maximum relaxation, and elevated systolic and diastolic blood pressure. Cilostazol seems to counteract the deleterious effects promoted by hypercholesterolemic diet, showing important anti-inflammatory and vasculoprotective properties possibly through the inhibition of the PLC-γ/PKC-α/p38-MAPK/IκB-α/NF-кB pathway and activation of the PKA/eNOS/PKG pathway. Cilostazol suppressed hypercholesterolemia-induced vascular dysfunction and inflammation. Our data suggest the potential repurposing of cilostazol as a pharmacological treatment for atherosclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]