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Cantú syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by gain-of-function (GoF) variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels and is characterized by low systemic vascular resistance, as well as tortuous, dilated, vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background and Purpose: The single layer of cells lining all blood vessels, the endothelium, is a sophisticated signal co‐ordination centre that controls a wide range of vascular functions including the regulation of blood pressure and blood flow. To co‐ordinate activities, communication among cells is required for tissue level responses to emerge. While a significant form of communication occurs by the propagation of signals between cells, the mechanism of propagation in the intact endothelium is unresolved. Experimental Approach: Precision signal generation and targeted cellular manipulation was used in conjunction with high spatiotemporal mesoscale Ca2+ imaging in the endothelium of intact blood vessels. Key Results: Multiple mechanisms maintain communication so that Ca2+ wave propagation occurs irrespective of the status of connectivity among cells. Between adjoining cells, regenerative IP3‐induced IP3 production transmits Ca2+ signals and explains the propagated vasodilation that underlies the increased blood flow accompanying tissue activity. The inositide is itself sufficient to evoke regenerative phospholipase C‐dependent Ca2+ waves across coupled cells. None of gap junctions, Ca2+ diffusion or the release of extracellular messengers is required to support this type of intercellular Ca2+ signalling. In contrast, when discontinuities exist between cells, ATP released as a diffusible extracellular messenger transmits Ca2+ signals across the discontinuity and drives propagated vasodilation. Conclusion and Implications: These results show that signalling switches underlie endothelial cell‐to‐cell signal transmission and reveal how communication is maintained in the face of endothelial damage. The findings provide a new framework for understanding wave propagation and cell signalling in the endothelium. [ABSTRACT FROM AUTHOR]

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13's role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10−4 M) and guanylate cyclase (ODQ at 10−5 M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on the activation of the nitric oxide–cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia. [ABSTRACT FROM AUTHOR]

Here we have shown for the first time altered expression of the vascular smooth muscle (VSM) KATP channel subunits in segments of the human internal mammary artery (HIMA) in patients with type-2 diabetes mellitus (T2DM). Functional properties of vascular KATP channels in the presence of T2DM, and the interaction between its subunits and endogenous ligands known to relax this vessel, were tested using the potassium (K) channels opener, pinacidil. HIMA is the most commonly used vascular graft in cardiac surgery. Previously it was shown that pinacidil relaxes HIMA segments through interaction with KATP (SUR2B/Kir6.1) vascular channels, but it is unknown whether pinacidil sensitivity is changed in the presence of T2DM, considering diabetes-induced vascular complications commonly seen in patients undergoing coronary artery bypass graft surgery (CABG). KATP subunits were detected in HIMA segments using Western blot and immunohistochemistry analyses. An organ bath system was used to interrogate endothelium-independent vasorelaxation caused by pinacidil. In pharmacological experiments, pinacidil was able to relax HIMA from patients with T2DM, with sensitivity comparable to our previous results. All three KATP subunits (SUR2B, Kir6.1 and Kir6.2) were observed in HIMA from patients with and without T2DM. There were no differences in the expression of the SUR2B subunit. The expression of the Kir6.1 subunit was lower in HIMA from T2DM patients. In the same group, the expression of the Kir6.2 subunit was higher. Therefore, KATP channels might not be the only method of pinacidil-induced dilatation of T2DM HIMA. T2DM may decrease the level of Kir6.1, a dominant subunit in VSM of HIMA, altering the interaction between pinacidil and those channels. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) produced by NADPH oxidases (NOX, a key source of ROS in vascular cells) are involved in the regulation of vascular tone, but this has been explored mainly for adult organisms. Importantly, the mechanisms of vascular tone regulation differ significantly in early postnatal ontogenesis and adulthood, while the vasomotor role of ROS in immature systemic arteries is poorly understood. We tested the hypothesis that the functional contribution of NADPH oxidase-derived ROS to the regulation of peripheral arterial tone is higher in the early postnatal period than in adulthood. We studied saphenous arteries from 10‐ to 15‐day‐old ("young") and 3‐ to 4-month-old ("adult") male rats using lucigenin-enhanced chemiluminescence, quantitative PCR, Western blotting, and isometric myography. We demonstrated that both basal and NADPH-stimulated superoxide anion radical (O 2 •−) production was significantly higher in the arteries from young in comparison to adult rats. Importantly, pan-inhibitor of NADPH oxidase VAS2870 (10 μM) reduced NADPH-induced O 2 •− production in arteries of young rats. Saphenous arteries of both young and adult rats demonstrated high levels of Nox2 and Nox4 mRNAs, while Nox1 and Nox3 mRNAs were not detected. The protein contents of NOX2 and NOX4 were significantly higher in arterial tissue of young compared to adult animals. Moreover, VAS2870 (10 μM) had no effect on methoxamine-induced contractile responses of adult arteries but decreased them significantly in young arteries; such effect of VAS2870 persisted after removal of the endothelium. Finally, NOX2 inhibitor GSK2795039 (10 μM), but not NOX1/4 inhibitor GKT137831 (10 μM) weakened methoxamine-induced contractile responses of arteries from young rats. Thus, ROS produced by NOX2 have a pronounced contractile influence in saphenous artery smooth muscle cells of young, but not adult rats, which is associated with the increased vascular content of NOX2 protein at this age. [Display omitted] • O 2.•− production is higher in saphenous artery of young compared to adult rats • NADPH-oxidases are important source of O 2.•− in saphenous artery of young rats • NOX2 and NOX4 contents are higher in arteries of young compared to adult rats. • O 2.•− produced by NOX2 promotes arterial contraction in young, but not adult rats [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration–response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms. [ABSTRACT FROM AUTHOR]

Here we have shown for the first time altered expression of the vascular smooth muscle (VSM) KATP channel subunits in segments of the human internal mammary artery (HIMA) in patients with type-2 diabetes mellitus (T2DM). Functional properties of vascular KATP channels in the presence of T2DM, and the interaction between its subunits and endogenous ligands known to relax this vessel, were tested using the potassium (K) channels opener, pinacidil. HIMA is the most commonly used vascular graft in cardiac surgery. Previously it was shown that pinacidil relaxes HIMA segments through interaction with KATP (SUR2B/Kir6.1) vascular channels, but it is unknown whether pinacidil sensitivity is changed in the presence of T2DM, considering diabetes-induced vascular complications commonly seen in patients undergoing coronary artery bypass graft surgery (CABG). KATP subunits were detected in HIMA segments using Western blot and immunohistochemistry analyses. An organ bath system was used to interrogate endothelium-independent vasorelaxation caused by pinacidil. In pharmacological experiments, pinacidil was able to relax HIMA from patients with T2DM, with sensitivity comparable to our previous results. All three KATP subunits (SUR2B, Kir6.1 and Kir6.2) were observed in HIMA from patients with and without T2DM. There were no differences in the expression of the SUR2B subunit. The expression of the Kir6.1 subunit was lower in HIMA from T2DM patients. In the same group, the expression of the Kir6.2 subunit was higher. Therefore, KATP channels might not be the only method of pinacidil-induced dilatation of T2DM HIMA. T2DM may decrease the level of Kir6.1, a dominant subunit in VSM of HIMA, altering the interaction between pinacidil and those channels.

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13’s role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10−4 M) and guanylate cyclase (ODQ at 10−5 M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13’s mechanism of action is dependent on the activation of the nitric oxide–cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13’s efficacy and safety as a therapeutic agent for managing preeclampsia.

It has been known for some time that Carbonic Anhydrase (CA, EC 4.2.1.1) plays a complex role in vascular function, and in the regulation of vascular tone. Clinically employed CA inhibitors (CAIs) are used primarily to lower intraocular pressure in glaucoma, and also to affect retinal blood flow and oxygen saturation. CAIs have been shown to dilate vessels and increase blood flow in both the cerebral and ocular vasculature. Similar effects of CAIs on vascular function have been observed in the liver, brain and kidney, while vessels in abdominal muscle and the stomach are unaffected. Most of the studies on the vascular effects of CAIs have been focused on the cerebral and ocular vasculatures, and in particular the retinal vasculature, where vasodilation of its vessels, after intravenous infusion of sulfonamide-based CAIs can be easily observed and measured from the fundus of the eye. The mechanism by which CAIs exert their effects on the vasculature is still unclear, but the classic sulfonamide-based inhibitors have been found to directly dilate isolated vessel segments when applied to the extracellular fluid. Modification of the structure of CAI compounds affects their efficacy and potency as vasodilators. CAIs of the coumarin type, which generally are less effective in inhibiting the catalytically dominant isoform hCA II and unable to accept NO, have comparable vasodilatory effects as the primary sulfonamides on pre-contracted retinal arteriolar vessel segments, providing insights into which CA isoforms are involved. Alterations of the lipophilicity of CAI compounds affect their potency as vasodilators, and CAIs that are membrane impermeant do not act as vasodilators of isolated vessel segments. Experiments with CAIs, that shed light on the role of CA in the regulation of vascular tone of vessels, will be discussed in this review. The role of CA in vascular function will be discussed, with specific emphasis on findings with the effects of CA inhibitors (CAI).

Reactive oxygen species (ROS) have been considered for many years as negative regulators in the cardiovascular system. Indeed, excessive production of ROS characterizes many cardiovascular diseases. The damaging effect of ROS can be especially pronounced in a newborn organism, since during this period their vasoconstrictor effect in pulmonary arteries remains as high as in pre-term fetus and the antioxidant systems have not yet formed. Therefore, in the first hours and days of independent life, pulmonary arteries tend to contract, primarily due to the low bioavailability of endothelial NO, which increases the risk of developing pulmonary hypertension in newborns. At the same time, during the perinatal period, ROS play an important role in the adaptive reactions of the circulatory system. ROS provide occlusion of the ductus arteriosus and separation of the pulmonary and systemic circulations soon after birth, and also contribute to the contraction of peripheral vessels during hypoxia, which often accompanies the delivery, and therefore provide priority blood supply to the brain in these conditions. The vasomotor effect of ROS is also pronounced in early postnatal ontogenesis, but it has a different character. In the first weeks of life, the action of ROS serves as one of the mechanisms for increasing endothelium-dependent relaxation of pulmonary vessels. In addition, during early postnatal ontogeny, ROS may play an important role in the regulation of systemic vascular tone. This review outlines the current understanding of the vasomotor role of ROS in the vessels of the pulmonary and systemic circulations and considers the mechanisms of ROS effects on the functioning of vascular endothelial and smooth muscle cells in the perinatal and early postnatal periods. [ABSTRACT FROM AUTHOR]

Dietary nitrate (NO 3 −) supplementation can enhance nitric oxide (NO) bioavailability and lower blood pressure (BP) in humans. The nitrite concentration ([NO 2 −]) in the plasma is the most commonly used biomarker of increased NO availability. However, it is unknown to what extent changes in other NO congeners, such as S-nitrosothiols (RSNOs), and in other blood components, such as red blood cells (RBC), also contribute to the BP lowering effects of dietary NO 3 −. We investigated the correlations between changes in NO biomarkers in different blood compartments and changes in BP variables following acute NO 3 − ingestion. Resting BP was measured and blood samples were collected at baseline, and at 1, 2, 3, 4 and 24 h following acute beetroot juice (∼12.8 mmol NO 3 −, ∼11 mg NO 3 −/kg) ingestion in 20 healthy volunteers. Spearman rank correlation coefficients were determined between the peak individual increases in NO biomarkers (NO 3 −, NO 2 −, RSNOs) in plasma, RBC and whole blood, and corresponding decreases in resting BP variables. No significant correlation was observed between increased plasma [NO 2 −] and reduced BP, but increased RBC [NO 2 −] was correlated with decreased systolic BP (r s = −0.50, P = 0.03). Notably, increased RBC [RSNOs] was significantly correlated with decreases in systolic (r s = −0.68, P = 0.001), diastolic (r s = −0.59, P = 0.008) and mean arterial pressure (r s = −0.64, P = 0.003). Fisher's z transformation indicated no difference in the strength of the correlations between increases in RBC [NO 2 −] or [RSNOs] and decreased systolic blood pressure. In conclusion, increased RBC [RSNOs] may be an important mediator of the reduction in resting BP observed following dietary NO 3 − supplementation. • Dietary nitrate (NO 3 −) supplementation elevates plasma nitrite concentration ([NO 2 −]) and can lower blood pressure (BP) in humans. • We investigated the correlations between changes in relevant NO congeners in different blood compartments and corresponding changes in BP variables following acute NO 3 − ingestion. • There was no significant correlation between increased plasma [NO 2 −] and reduced BP, but increased red blood cell [NO 2 −] was correlated with decreased systolic BP. • Notably, increased red blood cell S-nitrosothiol concentration ([RSNOs]) was significantly correlated with decreases in systolic, diastolic and mean arterial pressure. • Red blood cell [RSNOs] may be an important mediator of the reduction in resting BP observed following dietary NO 3 − supplementation in humans. [ABSTRACT FROM AUTHOR]

Background and Purpose: High‐fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca2+‐activated K+ (KCa) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with KCa channels in regulating coronary vascular tone in HFD mice requires further exploration. Experimental Approach: TRPV4 channel activity was assessed by fluorescent Ca2+ imaging. Interactions between TRPV4 and KCa3.1 channels were verified by co‐immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site‐directed mutagenesis. Endothelium‐specific TRPV4 knockout (TRPV4EC−/−) mice were used to study the effect of the interactions between TRPV4‐KCa3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. Key Results: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca2+‐sensitive K+ channel (KCa3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1‐heptadecanoyl‐2‐hydroxy‐sn‐glycero‐3‐phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4‐KCa3.1 channels and to improve coronary arterial function. Conclusion and Implications: Our data highlight the importance of coupling between TRPV4 and KCa3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is considered as the main complication of the cardiovascular system leading to vascular endothelial dysfunction (VED). Besides, melatonin (MEL) has been known to improve the vascular tone directly or indirectly with MEL receptors (MT1R and MT2R) and antioxidant properties, respectively. The rings were extracted from three groups including non-diabetes (non-DM), streptozotocin induced diabetes (STZ-induced DM) and STZ-induced DM treated with MEL (DM+MEL) in male albino rats. The experimental procedure includes thoracic aortic vascular reactivity of angiotensin 1-7 (Ang 1-7) and histological examination. The vascular reactivity was conducted across eight distinct groups, encompassing RO-31-8220 (5 µM), protein kinase C (PKC) inhibitor, Apocyanin [(APO, 10 micromolar (µM)], the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, rotenone (ROT 50 µM), mitochondrial complex I electron transport chain inhibitor, oxypurinol (OXY, 100 µM), xanthine oxidase inhibitor, PI-3065 (1 µM), phosphoinositide 3-kinases (PI3K) inhibitor, Ipatasertib (1 µM), protein kinase B (AKT) inhibitor, A779 (1 µM), the Mas receptor blocker and N(?)-nitro-L-arginine methyl ester (L-NAME 200 µM), the nitric oxide (NO) inhibitor pre-incubation. However, it is worth noting that the pre-incubation with OXY resulted in a notably significant rightward shift in this response. Conversely, in the STZ-induced DM group, there was a notable significant rightward shift observed in response to each of APO, ROT, and OXY. MEL appeared to regulate the vascular tone within Ang 1-7 modulation in STZ-induced DM rats. Therefore, MEL could offer many vascular benefits within Ang 1-7 under diabetic condition. [ABSTRACT FROM AUTHOR]

The adipokine chemerin may support blood pressure, evidenced by a fall in mean arterial pressure after whole body antisense oligonucleotide (ASO)-mediated knockdown of chemerin protein in rat models of normal and elevated blood pressure. Although the liver is the greatest contributor of circulating chemerin, liver-specific ASOs that abolished hepatic-derived chemerin did not change blood pressure. Thus, other sites must produce the chemerin that supports blood pressure. We hypothesize that the vasculature is a source of chemerin independent of the liver that supports arterial tone. RNAScope, PCR, Western blot analyses, ASOs, isometric contractility, and radiotelemetry were used in the Dahl salt-sensitive (SS) rat (male and female) on a normal diet. Retinoic acid receptor responder 2 (Rarres2) mRNA was detected in the smooth muscle, adventitia, and perivascular adipose tissue of the thoracic aorta. Chemerin protein was detected immunohistochemically in the endothelium, smooth muscle cells, adventitia, and perivascular adipose tissue. Chemerin colocalized with the vascular smooth muscle marker α-actin and the adipocyte marker perilipin. Importantly, chemerin protein in the thoracic aorta was not reduced when liver-derived chemerin was abolished by a liver-specific ASO against chemerin. Chemerin protein was similarly absent in arteries from a newly created global chemerin knockout in Dahl SS rats. Inhibition of the receptor Chemerin1 by the receptor antagonist CCX832 resulted in the loss of vascular tone that supports potential contributions of chemerin by both perivascular adipose tissue and the media. These data suggest that vessel-derived chemerin may support vascular tone locally through constitutive activation of Chemerin1. This posits chemerin as a potential therapeutic target in blood pressure regulation. NEW & NOTEWORTHY Vascular tunicas synthesizing chemerin is a new finding. Vascular chemerin is independent of hepaticderived chemerin. Vasculature from both males and females have resident chemerin. Chemerin1 receptor activity supports vascular tone. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H2S, H2O2, prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies. [ABSTRACT FROM AUTHOR]

The aim of this work was to study the contribution of the superoxide radical (О2●–) to the mechanisms underlying the dysfunction of coronary voltage-gated potassium (Kv) channels in rats with posttraumatic stress disorder (PTSD). The study was performed on 117 outbred white male rats Rattus muridae weighing 210–240 g. To reproduce the experimental PTSD analog, a modified predator presence simulation model was used (contact with cat feces for 10 days, 15 min daily). PTSD development was confirmed by behavioral changes of affected animals in the Open Field test. Coronary vascular tone was studied on the isolated, isotonically contracting Langendorff rat hearts continuously perfused with a Krebs-Henseleit solution. O2●– contribution to coronary vascular tone regulation was studied by adding its scavenger, Tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid), to a perfusion solution. The functional activity of Kv channels was assessed by the degree of increment in coronary perfusion pressure (CPP) in response to 4-aminopyridine (4-AP), a Kv channel blocker, also added to a perfusion solution. In rat blood serum, the levels of diene conjugates (DCs) and malondialdehyde (MDA), as well as catalase (CAT) and superoxide dismutase (SOD) activities, were determined by spectrophotometry, while C-reactive protein (CRP) and interleukin 1β (IL-1β) levels were assayed by immunoenzyme analysis. In isolated hearts of PTSD rats (PTSD group), at a constant volume flow rate (CVFR) of 10 mL/min, CPP was 30% lower than in the Control group. 4-AP increased CPP by 24% in the PTSD group and by 70% in the Control group. After Tiron addition to a perfusion solution, at the same CVFR of 10 mL/min, CPP in the PTSD group was 52% lower compared to the Control group. In the PTSD + Tiron + 4-AP group, 4-AP-induced CPP increment (71.5%) was comparable to that in the Control group. In PTSD rats, IL-1β, CRP, DC and MDA serum levels were, respectively, 3, 1.6, 3.3 and 3.6 times higher than in control rats, while SOD and CAT activities were, respectively, 27 and 59% lower than in control animals. Thus, it was found that in PTSD rats, the functional activity of coronary vascular Kv channels is reduced, with oxidative stress-induced O2●– overproduction being one of the key putative mechanisms of such a channelopathy. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of death globally, with CVDs accounting for nearly 30% of deaths worldwide each year. G-protein-coupled receptors (GPCRs) are the most prominent family of receptors on the cell surface, and play an essential regulating cellular physiology and pathology. Some GPCR antagonists, such as β-blockers, are standard therapy for the treatment of CVDs. In addition, nearly one-third of the drugs used to treat CVDs target GPCRs. All the evidence demonstrates the crucial role of GPCRs in CVDs. Over the past decades, studies on the structure and function of GPCRs have identified many targets for the treatment of CVDs. In this review, we summarize and discuss the role of GPCRs in the function of the cardiovascular system from both vascular and heart perspectives, then analyze the complex ways in which multiple GPCRs exert regulatory functions in vascular and heart diseases. We hope to provide new ideas for the treatment of CVDs and the development of novel drugs.

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces “local” changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels’ contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration–response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.

Arteriolar smooth muscle cells (SMCs) and capillary pericytes dynamically regulate blood flow in the central nervous system in the face of fluctuating perfusion pressures. Pressure-induced depolarization and Ca2+ elevation provide a mechanism for regulation of SMC contraction, but whether pericytes participate in pressure-induced changes in blood flow remains unknown. Here, utilizing a pressurized whole-retina preparation, we found that increases in intraluminal pressure in the physiological range induce contraction of both dynamically contractile pericytes in the arteriole-proximate transition zone and distal pericytes of the capillary bed. We found that the contractile response to pressure elevation was slower in distal pericytes than in transition zone pericytes and arteriolar SMCs. Pressure-evoked elevation of cytosolic Ca2+ and contractile responses in SMCs were dependent on voltage-dependent Ca2+ channel (VDCC) activity. In contrast, Ca2+ elevation and contractile responses were partially dependent on VDCC activity in transition zone pericytes and independent of VDCC activity in distal pericytes. In both transition zone and distal pericytes, membrane potential at low inlet pressure (20 mmHg) was approximately −40 mV and was depolarized to approximately −30 mV by an increase in pressure to 80 mmHg. The magnitude of whole-cell VDCC currents in freshly isolated pericytes was approximately half that measured in isolated SMCs. Collectively, these results indicate a loss of VDCC involvement in pressure-induced constriction along the arteriole-capillary continuum. They further suggest that alternative mechanisms and kinetics of Ca2+ elevation, contractility, and blood flow regulation exist in central nervous system capillary networks, distinguishing them from neighboring arterioles. [ABSTRACT FROM AUTHOR]

ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal cell functions is a new therapeutic avenue. In this paper, we describe new inhibitors of NADPH oxidase (NOX), a key enzyme in many cells of the tumor microenvironment. The first inhibitor, called Nanoshutter-1, NS1, decreased the level of tumor-promoting "M2" macrophages differentiated from human blood monocytes. NS1 disrupted the active NADPH oxidase-2 (NOX2) complex at the membrane and in the mitochondria of the macrophages, as shown by confocal microscopy. As one of the characteristics of tumor invasion is hypoxia, we tested whether NS1 would affect vascular reactivity by reducing ROS or NO levels in wire and pressure myograph experiments on isolated blood vessels. The results show that NS1 vasodilated blood vessels and would likely reduce hypoxia. Finally, as both NOX2 and NOX4 are key proteins in tumors and their microenvironment, we investigated whether NS1 would probe these proteins differently. Models of NOX2 and NOX4 were generated by homology modeling, showing structural differences at their C-terminal NADPH site, in particular in their last Phe. Thus, the NADPH site presents an unexploited chemical space for addressing ligand specificity, which we exploited to design a novel NOX2-specific inhibitor targeting variable NOX2 residues. With the proper smart vehicle to target specific cells of the microenvironment as TAMs, NOX2-specific inhibitors could open the way to new precision therapies. [ABSTRACT FROM AUTHOR]

Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca2+-activated K+ (KCa) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. KCa channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by KCa channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of KCa channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]

The incidence of cardiovascular diseases is continuously increasing around the world. Therefore, the study of new methods for diagnosing cardiovascular diseases is very important. Early diagnosis and evaluation of the effectiveness of treatments are among the most important tasks. In this work, we study changes in vascular compliance and vascular tone of the lower extremities in a patient diagnosed with an early stage of varicose veins. The study is based on recording the bioimpedance signals of the lower extremities and their parts using the Rheo-32 multichannel device. Registration in the monitoring system takes place in two stages: the first in a state of relaxation, and the second after applying a local massage on one of the legs for five minutes. The results indicate a change in the type of vascular tone of the lower extremities after the massage, while the type of vascular tone changes and shifts on average towards the normotonic type. The method proposed in this study makes it possible to quantitatively and qualitatively assess changes in the tone of the vessels of the extremities. [ABSTRACT FROM AUTHOR]

Maintaining endothelial cell (EC) and vascular smooth muscle cell (VSMC) integrity is an important component of human health and disease because both EC and VSMC regulate various functions, including vascular tone control, cellular adhesion, homeostasis and thrombosis regulation, proliferation, and vascular inflammation. Diverse stressors affect functions in both ECs and VSMCs and abnormalities of functions in these cells play a crucial role in cardiovascular disease initiation and progression. Toll-like receptors (TLRs) are important detectors of pathogen-associated molecular patterns derived from various microbes and viruses as well as damage-associated molecular patterns derived from damaged cells and perform innate immune responses. Among TLRs, several studies reveal that TLR3 plays a key role in initiation, development and/or protection of diseases, and an emerging body of evidence indicates that TLR3 presents components of the vasculature, including ECs and VSMCs, and plays a functional role. An agonist of TLR3, polyinosinic-polycytidylic acid [poly (I:C)], affects ECs, including cell death, inflammation, chemoattractant, adhesion, permeability, and hemostasis. Poly (I:C) also affects VSMCs including inflammation, proliferation, and modulation of vascular tone. Moreover, alterations of vascular function induced by certain molecules and/or interventions are exerted through TLR3 signaling. Hence, we present the association between TLR3 and vascular function according to the latest studies. [ABSTRACT FROM AUTHOR]

Patients with hypertension develop hemodynamic instability more frequently during anesthesia—particularly post-induction. Therefore, different monitoring methods may be required in patients with hypertension. Perfusion index—the ratio of the pulsatile blood flow to the non-pulsatile static blood flow in a patient's peripheral tissues, such as the fingers or ears—can show the hemodynamic status of the patient in a non-invasive way. Among the sites used for measuring the perfusion index, it is assumed that the ear is more reliable than the finger for hemodynamic monitoring, because proximity to the brain ensures appropriate perfusion. We hypothesized that the low value of preoperative ear PI could be a predictor of post-induction hypotension in patients with hypertension. Thirty patients with hypertension were enrolled. The perfusion index and pleth variability index were measured using the ear, finger, and blood pressure, and heart rate was recorded to monitor hypotension. After insertion of the supraglottic airway, 20 patients developed post-induction hypotension. Those who developed hypotension showed a significantly lower preoperative perfusion index of the ear. The preoperative perfusion index of the ear could predict post-induction hypotension in patients with hypertension. [ABSTRACT FROM AUTHOR]

Background: The mechanism of the perivascular adipose tissue (PVAT) anticontractile effect is well characterized in rodent visceral vascular beds; however, little is known about the mechanism of PVAT anticontractile function in subcutaneous vessels. In addition, we have previously shown that PVAT anticontractile function is nitric oxide synthase (NOS) dependent but have not investigated the roles of NOS isoforms. Objective: Here, we examined PVAT anticontractile function in the mouse gracilis artery, a subcutaneous fat depot, in lean control and obese mice and investigated the mechanism in comparison to a visceral depot. Method: Using the wire myograph, we generated responses to noradrenaline and electrical field stimulation in the presence of pharmacological tools targeting components of the known PVAT anticontractile mechanism. In addition, we performed ex vivo "fat transplants" in the organ bath. Results: The mechanism of PVAT anticontractile function is similar between subcutaneous and visceral PVAT depots. Both endothelial and neuronal NOS isoforms mediated the PVAT anticontractile effect. Loss of PVAT anticontractile function in obesity is independent of impaired vasoreactivity, and function can be restored in visceral PVAT by NOS activation. Conclusions: Targeting NOS isoforms may be useful in restoring PVAT anticontractile function in obesity, ameliorating increased vascular tone, and disease. [ABSTRACT FROM AUTHOR]

Given the interconnection between depressive and cardiovascular disorders, we investigated whether antidepressant treatment (fluoxetine) modifies the serotonergic influence on rat vascular noradrenergic outflow. Twelve-week-old male Wistar rats received fluoxetine treatment (10 mg/kg/day; p.o.) for 14 days; then, they were pithed and prepared for sympathetic stimulation. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1, 0.5, 1, and 5 Hz) or i.v. noradrenaline (NA; 0.01, 0.05, 0.1, and 0.5 μg/kg). In fluoxetine-treated group, the electrical-induced vasoconstrictions were lower compared to non-treated rats. Intravenous infusion of 5-HT (10 μg/kg/min) inhibited the sympathetically-induced vasoconstrictions. Only 5-CT, 8-OH-DPAT and L-694,247 (5-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) mimicked 5-HT-induced inhibition, while α-methyl-5-HT (5-HT2 agonist) increased the vasopressor responses. The inhibitory effect of 5-HT was: a) no modified by SB269970 (5-HT7 antagonist); b) abolished by WAY-100,635 (5-HT1A antagonist) plus LY310762 (5-HT1D antagonist); and c) potentiated by ritanserin (5-HT2A receptor antagonist). The vasoconstrictions induced by exogenous NA were not modified by 5-CT but were increased by α-methyl-5-HT. Our results suggest that fluoxetine treatment decreases NA release at vascular level and changes 5-HT modulation on rat vascular noradrenergic neurotransmission, inducing sympatho-inhibition via prejunctional 5-HT1A/1D receptors, and sympatho-potentiation via pre and/or postjunctional 5-HT2A receptors.

Introduction: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response. Methods: Male rats, on day 0, were treated intraperitoneally with either DSP4 (50 mg/kg body weight) (DSP), an LC-NA specific neurotoxin, or normal saline (SAL). On day 10, animals were surgically prepared with jugular vein (hypothalamic-pituitary-adrenal [HPA] axis) or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress (transient hemorrhage [14 mL/kg body weight] or air puff-startle), and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. Results: In DSP rats compared to SAL rats, (1) regional brain norepinephrine was decreased, but there was no change in median eminence or olfactory bulb CRF content; (2) during HPA axis acrophase, the plasma corticosterone response was blunted; (3) after hemorrhage and air puff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; (4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and (5) after hemorrhage, hemodynamics exhibited asynchronous responses. Conclusion: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed. [ABSTRACT FROM AUTHOR]

The change in the diameter of small arteries and arterioles is a key mechanism for regulating the resistance of the vascular bed and blood pressure and blood flow in organs and tissues. The tone of arterial smooth muscle cells (SMC) depends on the level of membrane potential (MP), which, in turn, is determined by the balance of depolarizing and hyperpolarizing currents. The main hyperpolarizing current of SMC is the outward potassium current. Activation and opening of potassium channels counteract depolarization and inhibit calcium entry into the cell and contraction. Thus, potassium channels play an anticonstrictor role in the arteries. TASK-1 channels, members of the two-pore domain potassium channel family (K2P), have relatively recently been described in the vasculature. It is known that TASK-1 channels mediate outward potassium leakage current in arterial SMC. In addition, TASK-1 channels are regulated by a number of stimuli: their activity augments with an increase of extracellular pH, decreases in hypoxia, and can also change under the influence of inhalation/local anesthetics and vasoactive substances. TASK-1 channels play an important role in the regulation of arterial tone in pulmonary circulation; their dysfunction is one of the causes of arterial pulmonary hypertension development. In systemic arteries of adult animals, the influence of TASK-1 channels under normal pH is small or absent, but it can manifest itself under conditions of extracellular alkalosis. In addition, the anticontractile role of TASK-1 channels is more pronounced at the early stages of postnatal development. This review outlines the current understanding of the functional role and regulation of TASK-1 channels in the vascular system. [ABSTRACT FROM AUTHOR]

Keywords: endothelial cell; metabolism; oxidative phosphorylation; mitochondria; Ca 2+ signaling; vascular tone EN endothelial cell metabolism oxidative phosphorylation mitochondria Ca 2+ signaling vascular tone 1 3 3 04/03/23 20230301 NES 230301 A Perspective on: "Mitochondrial ATP Production Is Required for Endothelial Cell Control of V... Metabolism dictates how cells, tissues, and organs operate - the vasculature is no exception. Whether glycolysis or oxidative phosphorylation dictates EC energy production in mature blood vessels and whether EC metabolism affects vascular tone control are not fully understood. Mitochondrial ATP Controls Ca 2+ Release Second, Wilson and colleagues showed that mitochondrial ATP production is crucial for distinct endothelium-dependent vasodilatory pathways. [Extracted from the article]

Objective: Several metabolites from the kynurenine pathway of tryptophan metabolism play a critical role in vascular function and vascular wall remodeling. This study aimed to test whether metabolite kynurenic acid (KYNA) from the kynurenine pathway relaxes blood vessels. Approach and results: We employed histological staining, in vitro cell culture, Western blotting, real-time PCR, and nitric oxide detection to validate kynurenine aminotransferase (KAT) localization in the vasculature as well as KYNA action on endothelial cells. We also detected vascular reactivity by organ chamber and monitored blood pressure by telemetry to investigate the regulation effect of KYNA on vascular tone. The results presented that perivascular adipose tissue (PVAT) from mice thoracic aorta had robust staining of anti-KAT1 and KYNA than PVAT from the abdominal aorta and mesenteric artery, which is consistent with the expression profile of brown adipocyte marker uncoupling protein 1. KYNA, metabolized from kynurenine by KAT, relaxed pre-contracted both aortic ring and mesenteric artery. In addition, KYNA derived from KAT in PVAT participates in the cross-talk between PVAT and vessel by mediating PVAT inhibition on agonist-induced thoracic aorta contraction. Furthermore, intraperitoneal injection of KYNA in mice reduced blood pressure. The vessel relaxation effect of KYNA was through the endothelium-dependent PI3K-Akt-eNOS pathway. Finally, the high-fat diet decreased KAT1 expression in perithoracic aortic fat and led to KYNA reduction in blood. Conclusions: Our research identified KYNA generated by KAT as a novel perivascular brown adipocyte-derived vascular relaxation factor and suggests that KYNA reduction is a critical event in vascular dysfunction under obese condition.

AuNPs are synthesized through several methods to tune their physicochemical properties. Although AuNPs are considered biocompatible, a change in morphology or properties can modify their biological impact. In this work, AuNPs (~12 to 16 nm) capping with either sodium citrate (CA) or gallic acid (GA) were evaluated in a rat aorta ex vivo model, which endothelial inner layer surface is formed by glycocalyx (hyaluronic acid, HA, as the main component), promoting vascular processes, most of them dependent on nitric oxide (NO) production. Results showed that contractile effects were more evident with AuNPsCA, while dilator effects predominated with AuNPsGA. Furthermore, treatments with AuNPsCA and AuNPsGA in the presence or absence of glycocalyx changed the NO levels, differently. This work contributes to understanding the biological effects of AuNPs with different capping agents, as well as the key role that of HA in the vascular effects induced by AuNPs in potential biomedical applications.

• The regulation of Ca2+ homeostasis by TRPs in vascular cells is reviewed. • TRP-mediated regulation of vascular tone under physiological and pathophysiological conditions is presented. • Potential therapeutic approaches to tackle abnormal vascular tone due to TRP dysfunction is discussed. Vascular tone is a major element in the control of hemodynamics. Transient receptor potential (TRP) channels conducting monovalent and/or divalent cations (e.g. Na+ and Ca2+) are expressed in the vasculature. Accumulating evidence suggests that TRP channels participate in regulating vascular tone by regulating intracellular Ca2+ signaling in both vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Aberrant expression/function of TRP channels in the vasculature is associated with vascular dysfunction in systemic/pulmonary hypertension and metabolic syndromes. This review intends to summarize our current knowledge of TRP-mediated regulation of vascular tone in both physiological and pathophysiological conditions and to discuss potential therapeutic approaches to tackle abnormal vascular tone due to TRP dysfunction. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H2S, H2O2, prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies.

Aim: TASK-1 channels are established regulators of pulmonary artery tone but their contribution to the regulation of vascular tone in systemic arteries is poorly understood. We tested the hypothesis that TASK-1 channel functional impact differs among systemic vascular beds, that this is associated with differences in their expression and may increase with alkalization of the extracellular environment. Therefore, we evaluated the expression level of TASK-1 channels and their vasomotor role in mesenteric and renal arteries. Methods: Pulmonary, mesenteric and renal arteries from male Wistar rats were used for TASK-1 channel mRNA (qPCR) and protein content (Western blotting) measurements. The functional role of TASK-1 channels was studied by wire myography using the TASK-1 channel blocker AVE1231. In some experiments, the endothelium was removed with a rat whisker. Results: Expression levels of both mRNA and protein of the TASK-1 channel pore-forming subunit were highest in pulmonary arteries, lowest in mesenteric arteries and had an intermediate value in renal arteries. Blockade of TASK-1 channels by 1 µM AVE1231 increased U46619-induced contractile responses of pulmonary arteries but did not affect basal tone and contractile responses to methoxamine of mesenteric and renal arteries at physiological extracellular pH (pHo = 7.41). At alkaline extracellular pH = 7.75 (increase of NaHCO3 to 52 mM) AVE1231 evoked the development of basal tone and increased contractile responses to low concentrations of methoxamine in renal but not mesenteric arteries. This effect was independent of the endothelium. Conclusion: In the rat systemic circulation, TASK-1 channels are abundant in renal arteries and have an anticontractile function under conditions of extracellular alkalosis. [ABSTRACT FROM AUTHOR]

Although metabolic acidosis is associated with numerous pathophysiological conditions and its vasorelaxation effects have been well described in different animal and culture models, the molecular mechanisms of acidosis-induced vasorelaxation are not fully understood. Mesenteric artery models have been used extensively to examine the vascular response to various pathophysiological conditions. Our previous studies and several other reports have suggested the vascular responses of goat mesenteric arteries and human arteries to various stimuli, including acidic stress, are highly similar. In this study, to further identify the signaling molecules responsible for altered vasoreactivity in response to acidic pH, we examined the proteomic profile of acid stress-induced vasorelaxation using a goat mesenteric artery model. The vascular proteomes under acidic pH were compared using 2D-GE with 7 cm IPG strips and mini gels, LC-MS/MS, and MALDI TOF MS. The unique proteins identified by mass spectroscopy were actin, transgelin, WD repeat-containing protein 1, desmin, tropomyosin, ATP synthase β, Hsp27, aldehyde dehydrogenase, pyruvate kinase, and vitamin K epoxide reductase complex subunit 1-like protein. Out of five protein spots identified as actin, three were upregulated > 2-fold. ATP synthase β was also upregulated (2.14-fold) under acid stress. Other actin-associated proteins upregulated were transgelin, desmin, and WD repeat-containing protein 1. Isometric contraction studies revealed that both receptor-mediated (histamine) and non-receptor-mediated (KCl) vasocontraction were attenuated, whereas acetylcholine-induced vasorelaxation was augmented under acidosis. Overall, the altered vasoreactivity under acidosis observed in the functional studies could possibly be attributed to the increase in expression of actin and ATP synthase β. [ABSTRACT FROM AUTHOR]

Aim: TASK-1 channels are established regulators of pulmonary artery tone but their contribution to the regulation of vascular tone in systemic arteries is poorly understood. We tested the hypothesis that TASK-1 channel functional impact differs among systemic vascular beds, that this is associated with differences in their expression and may increase with alkalization of the extracellular environment. Therefore, we evaluated the expression level of TASK-1 channels and their vasomotor role in mesenteric and renal arteries.Methods: Pulmonary, mesenteric and renal arteries from male Wistar rats were used for TASK-1 channel mRNA (qPCR) and protein content (Western blotting) measurements. The functional role of TASK-1 channels was studied by wire myography using the TASK-1 channel blocker AVE1231. In some experiments, the endothelium was removed with a rat whisker.Results: Expression levels of both mRNA and protein of the TASK-1 channel pore-forming subunit were highest in pulmonary arteries, lowest in mesenteric arteries and had an intermediate value in renal arteries. Blockade of TASK-1 channels by 1 µM AVE1231 increased U46619-induced contractile responses of pulmonary arteries but did not affect basal tone and contractile responses to methoxamine of mesenteric and renal arteries at physiological extracellular pH (pHo = 7.41). At alkaline extracellular pH = 7.75 (increase of NaHCO3 to 52 mM) AVE1231 evoked the development of basal tone and increased contractile responses to low concentrations of methoxamine in renal but not mesenteric arteries. This effect was independent of the endothelium.Conclusion: In the rat systemic circulation, TASK-1 channels are abundant in renal arteries and have an anticontractile function under conditions of extracellular alkalosis.

This research is aimed at studying the effect of physical factors of the natural environmental on the cognitive functions and physiological adaptation mechanisms of cadets at a naval institute with preuniversity military training experience. The test sample includes 42 freshman cadets at the Military Training and Research Center at the Naval Academy. Electroencephalography, analysis of heart rate variability (HRV), and finger photoplethysmography were used simultaneously with psychophysiological tests. The cadets were examined in the fall in the first semester of their first year of education. It is established that the increase in the class A X-ray background radiation positively correlates with the efficiency of spatial orientation. The slightly increased solar activity increases the efficiency of selective attention, verbal–logical thinking and short-term memory, and provokes an increase in the bioelectric activity of the sensorimotor cortex in the left hemisphere of the brain. Simultaneously, there is a decrease in the activity in the sensorimotor cortex of the right hemisphere correlating with the increased electron stream of more than 2 MeV and at lower atmospheric air temperatures. The increased atmospheric pressure, solar and geomagnetic activity, and the decrease in the energy of cosmic rays are accompanied by reduced HRV and higher loading of adaptation mechanisms in performing all cognitive tasks. The increased proton stream of more than 10 MeV positively correlates with the vascular tone in the state of relative quiescence. The increase in class A X-ray background radiation correlates with the decrease in the vascular tone when performing sensorimotor tasks of tracking moving objects. [ABSTRACT FROM AUTHOR]

More than 30 years have passed since endothelial nitric oxide synthesis was described using the umbilical artery and vein endothelium. That seminal report set the cornerstone for unveiling the molecular aspects of endothelial function. In parallel, the understanding of placental physiology has gained growing interest, due to its crucial role in intrauterine development, with considerable long‐term health consequences. This review discusses the evidence for nitric oxide (NO) as a critical player of placental development and function, with a special focus on endothelial nitric oxide synthase (eNOS) vascular effects. Also, the regulation of eNOS‐dependent vascular responses in normal pregnancy and pregnancy‐related diseases and their impact on prenatal and postnatal vascular health are discussed. Recent and compelling evidence has reinforced that eNOS regulation results from a complex network of processes, with novel data concerning mechanisms such as mechano‐sensing, epigenetic, posttranslational modifications, and the expression of NO‐ and l‐arginine‐related pathways. In this regard, most of these mechanisms are expressed in an arterial‐venous‐specific manner and reflect traits of the fetal systemic circulation. Several studies using umbilical endothelial cells are not aimed to understand placental function but general endothelial function, reinforcing the influence of the placenta on general knowledge in physiology. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction plays a key role in the initial development of atherosclerosis. The presence of atherosclerosis by ultrasound examination of the carotid arteries is associated with an increased risk of development of coronary heart disease (CHD) by 1.2% –3.3% per year. The study of the relationship between morphological and functional vascular alterations is an important step toward an improvement of prognostic assessment of the risk of cardiovascular diseases (CVD) and the development of new tools for their prevention. We aimed to perform a systematic review of published studies evaluating the relationship between flow-mediated vasodilation (FMD) during reactive hyperemia test and carotid artery intima-media thickness (IMT). Material and methods. Publications on selected topic were analyzed from 2000 to 2019. We used various Internet resources such as PubMed (https://www.ncbi.nlm.nih.gov/pubmed), Google Scholar (https://scholar.google.ru), the scientific electronic library eLIBRARY.ru (https://elibrary.ru) and major Russian cardiology journals. Results. The analysis of the literature showed that a relationship between a decrease of FMD and an increase of IMT is consistently found in patients with type 2 diabetes mellitus, with verified atherosclerosis of different locations (including CHD and peripheral arterial atherosclerosis), and arterial hypertension. However, these studies were conducted predominantly on small clinical groups (from 10 to 136 people). Few large studies (more than 1000 people) among subjects with arterial hypertension and type 2 diabetes mellitus did not show any convincing relationship between IMT and FMD. In the current literature there is a lack of large studies on the problem, and the data of existing studies are contradictory. New larger studies on this issue are required in various populations and in a wide age range. Conclusion. The studying of association between phenotypes of vasodilation function and structural changes of the vascular wall (for example, between FMD and IMT) remains topical for prognostic assessments of the risk of developing of cardiovascular diseases.

Stimulating collateral arteriogenesis is an attractive therapeutic target for peripheral artery disease (PAD). However, the potency of arteriogenesis-stimulation in animal models has not been matched with efficacy in clinical trials. This may be because the presence of enlarged collaterals is not sufficient to relieve symptoms of PAD, suggesting that collateral function is also important. Specifically, collaterals are the primary site of vascular resistance following arterial occlusion, and impaired collateral vasodilation could impact downstream tissue perfusion and limb function. Therefore, we evaluated the effects of arteriogenesis on collateral vascular reactivity. Following femoral artery ligation in the mouse hindlimb, collateral functional vasodilation was impaired at day 7 (17 ± 3 vs. 60 ± 8%) but restored by day 28. This impairment was due to a high resting diameter (73 ± 4 μm at rest vs. 84 ± 3 μm dilated), which does not appear to be a beneficial effect of arteriogenesis because increasing tissue metabolic demand through voluntary exercise decreased resting diameter and restored vascular reactivity at day 7. The high diameter in sedentary animals was not due to sustained NO-dependent vasodilation or defective myogenic constriction, as there were no differences between the enlarged and native collaterals in response to eNOS inhibition with L-NAME or L-type calcium channel inhibition with nifedipine, respectively. Surprisingly, in the context of reduced vascular tone, vasoconstriction in response to the α-adrenergic agonist norepinephrine was enhanced in the enlarged collateral (−62 ± 2 vs. −37 ± 2%) while vasodilation in response to the α-adrenergic antagonist prazosin was reduced (6 ± 4% vs. 22 ± 16%), indicating a lack of α-adrenergic receptor activation by endogenous norepinephrine and suggesting a denervation of the neuroeffector junction. Staining for tyrosine hydroxylase demonstrated sympathetic denervation, with neurons occupying less area and located further from the enlarged collateral at day 7. Inversely, MMP2 presence surrounding the enlarged collateral was greater at day 7, suggesting that denervation may be related to extracellular matrix degradation during arteriogenesis. Further investigation on vascular wall maturation and the functionality of enlarged collaterals holds promise for identifying novel therapeutic targets to enhance arteriogenesis in patients with PAD.

ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal cell functions is a new therapeutic avenue. In this paper, we describe new inhibitors of NADPH oxidase (NOX), a key enzyme in many cells of the tumor microenvironment. The first inhibitor, called Nanoshutter-1, NS1, decreased the level of tumor-promoting “M2” macrophages differentiated from human blood monocytes. NS1 disrupted the active NADPH oxidase-2 (NOX2) complex at the membrane and in the mitochondria of the macrophages, as shown by confocal microscopy. As one of the characteristics of tumor invasion is hypoxia, we tested whether NS1 would affect vascular reactivity by reducing ROS or NO levels in wire and pressure myograph experiments on isolated blood vessels. The results show that NS1 vasodilated blood vessels and would likely reduce hypoxia. Finally, as both NOX2 and NOX4 are key proteins in tumors and their microenvironment, we investigated whether NS1 would probe these proteins differently. Models of NOX2 and NOX4 were generated by homology modeling, showing structural differences at their C-terminal NADPH site, in particular in their last Phe. Thus, the NADPH site presents an unexploited chemical space for addressing ligand specificity, which we exploited to design a novel NOX2-specific inhibitor targeting variable NOX2 residues. With the proper smart vehicle to target specific cells of the microenvironment as TAMs, NOX2-specific inhibitors could open the way to new precision therapies.

The incidence of cardiovascular diseases is continuously increasing around the world. Therefore, the study of new methods for diagnosing cardiovascular diseases is very important. Early diagnosis and evaluation of the effectiveness of treatments are among the most important tasks. In this work, we study changes in vascular compliance and vascular tone of the lower extremities in a patient diagnosed with an early stage of varicose veins. The study is based on recording the bioimpedance signals of the lower extremities and their parts using the Rheo-32 multichannel device. Registration in the monitoring system takes place in two stages: the first in a state of relaxation, and the second after applying a local massage on one of the legs for five minutes. The results indicate a change in the type of vascular tone of the lower extremities after the massage, while the type of vascular tone changes and shifts on average towards the normotonic type. The method proposed in this study makes it possible to quantitatively and qualitatively assess changes in the tone of the vessels of the extremities.

Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca2+-activated K+ (KCa) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. KCa channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by KCa channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of KCa channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions.