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Aim: Fluid and macromolecule transport from the interstitium into and through lymphatic vessels is necessary for tissue homeostasis. While lymphatic capillary structure suggests that passive, paracellular transport would be the predominant route of macromolecule entry, active caveolae‐mediated transcellular transport has been identified in lymphatic endothelial cells (LECs) in vitro. Caveolae also mediate a wide array of endothelial cell processes, including nitric oxide regulation. Thus, how does the lack of caveolae impact "lymphatic function"? Methods: Various aspects of lymphatic transport were measured in mice constitutively lacking caveolin‐1 ("CavKO"), the protein required for caveolae formation in endothelial cells, and in mice with a LEC‐specific Cav1 gene deletion (Lyve1‐Cre x Cav1flox/flox; "LyCav") and ex vivo in their vessels and cells. Results: In each model, lymphatic architecture was largely unchanged. The lymphatic conductance, or initial tissue uptake, was significantly higher in both CavKO mice and LyCav mice by quantitative microlymphangiography and the permeability to 70 kDa dextran was significantly increased in monolayers of LECs isolated from CavKO mice. Conversely, transport within the lymphatic system to the sentinel node was significantly reduced in anaesthetized CavKO and LyCav mice. Isolated, cannulated collecting vessel studies identified significantly reduced phasic contractility when lymphatic endothelium lacks caveolae. Inhibition of nitric oxide synthase was able to partially restore ex vivo vessel contractility. Conclusion: Macromolecule transport across lymphatics is increased with loss of caveolae, yet phasic contractility reduced, resulting in reduced overall lymphatic transport function. These studies identify lymphatic caveolar biology as a key regulator of active lymphatic transport functions. [ABSTRACT FROM AUTHOR]

The researchers found that after nitrate supplementation, plasma nitrate, and nitrite increased significantly, but blood pressure remained unchanged. The kidney is one of the human organs that harbors a huge number of distinct cell types. They measured a number of parameters such as renal nitrate clearance and fractional excretion of nitrate as well as glomerular filtration rate based on creatinine clearance using the 24 h urine collection and 24 h ambulatory blood pressure measurement. The inorganic anions nitrate and nitrite are oxidation products of NO that have often been used as an index of NO generation.1 The aim of a study by Sundqvist et al, was to explore potential sex differences in renal nitrate handling during low and high dietary nitrate intake. [Extracted from the article]

Aim: Loss of dystrophin causes oxidative stress and affects nitric oxide synthase‐mediated vascular function in striated muscle. Because tetrahydrobiopterin is an antioxidant and co‐factor for nitric oxide synthase, we tested the hypothesis that tetrahydrobiopterin would be low in mdx mice and humans deficient for dystrophin. Methods: Tetrahydrobiopterin and its metabolites were measured at rest and in response to exercise in Duchenne and Becker muscular dystrophy patients, age‐matched male controls as well as wild‐type, mdx and mdx mice transgenically overexpressing skeletal muscle‐specific dystrophins. Mdx mice were also supplemented with tetrahydrobiopterin and pathophysiology was assessed. Results: Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin + tetrahydrobiopterin/specific gravity1.020 compared to unaffected age‐matched males and Becker muscular dystrophy patients. Mdx mice had low urinary and skeletal muscle dihydrobiopterin + tetrahydrobiopterin compared to wild‐type mice. Overexpression of dystrophins that localize neuronal nitric oxide synthase restored dihydrobiopterin + tetrahydrobiopterin in mdx mice to wild‐type levels while utrophin overexpression did not. Mdx mice and Duchenne muscular dystrophy patients did not increase tetrahydrobiopterin during exercise and in mdx mice tetrahydrobiopterin deficiency was likely because of lower levels of sepiapterin reductase in skeletal muscle. Tetrahydrobiopterin supplementation improved skeletal muscle strength, resistance to fatiguing and injurious contractions in vivo, increased utrophin and capillary density of skeletal muscle and lowered cardiac muscle fibrosis and left ventricular wall thickness in mdx mice. Conclusion: These data demonstrate that impaired tetrahydrobiopterin synthesis is associated with dystrophin loss and treatment with tetrahydrobiopterin improves striated muscle histopathology and skeletal muscle function in mdx mice. [ABSTRACT FROM AUTHOR]

Aims: In patients with renal disease, high serum phosphate shows a relationship with cardiovascular risk. We speculate that high phosphate (HP) impairs arterial vasodilation via the endothelium and explore potential underlying mechanisms. Methods: Isolated vessel relaxation, endothelial function, glomerular filtration rate (GFR), oxidative stress status and protein expression were assessed in HP diet mice. Mitochondrial function and protein expression were assessed in HP‐treated human umbilical vein endothelial cells (HUVECs). Results: High phosphate (1.3%) diet for 12 weeks impaired endothelium‐dependent relaxation in mesenteric arteries, kidney interlobar arteries and afferent arterioles; reduced GFR and the blood pressure responses to acute administration of acetylcholine. The PPARα/LKB1/AMPK/eNOS pathway was attenuated in the endothelium of mesenteric arteries from HP diet mice. The observed vasodilatory impairment of mesenteric arteries was ameliorated by PPARα agonist WY‐14643. The phosphate transporter PiT‐1 knockdown prevented HP‐mediated suppression of eNOS activity by impeding phosphorus influx in HUVECs. Endothelium cytoplasmic and mitochondrial reactive oxygen species (ROS) were increased in HP diet mice. Moreover HP decreased the expression of mitochondrial‐related antioxidant genes. Finally, mitochondrial membrane potential and PGC‐1α expression were reduced by HP treatment in HUVECs, which was partly restored by AMPKα agonist. Conclusions: HP impairs endothelial function by reducing NO bioavailability via decreasing eNOS activity and increasing mitochondrial ROS, in which the AMPK‐related signalling pathways may play a key role. [ABSTRACT FROM AUTHOR]

Aim: Chromogranin A (CgA), a 439‐residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA1‐373 proangiogenic fragment. The present work investigated the possibility that human CgA1‐373 influences the mammalian cardiac performance, evaluating the role of its C‐terminal sequence. Methods: Haemodynamic assessment was performed on an ex vivo Langendorff rat heart model, while mechanistic studies were performed using perfused hearts, H9c2 cardiomyocytes and in silico. Results: On the ex vivo heart, CgA1‐373 elicited direct dose‐dependent negative inotropism and vasodilation, while CgA1‐372, a fragment lacking the C‐terminal R373 residue, was ineffective. Antibodies against the PGPQLR373 C‐terminal sequence abrogated the CgA1‐373‐dependent cardiac and coronary modulation. Ex vivo studies showed that CgA1‐373‐dependent effects were mediated by endothelium, neuropilin‐1 (NRP1) receptor, Akt/NO/Erk1,2 pathways, nitric oxide (NO) production and S‐nitrosylation. In vitro experiments on H9c2 cardiomyocytes indicated that CgA1‐373 also induced eNOS activation directly on the cardiomyocyte component by NRP1 targeting and NO involvement and provided beneficial action against isoproterenol‐induced hypertrophy, by reducing the increase in cell surface area and brain natriuretic peptide (BNP) release. Molecular docking and all‐atom molecular dynamics simulations strongly supported the hypothesis that the C‐terminal R373 residue of CgA1‐373 directly interacts with NRP1. Conclusion: These results suggest that CgA1‐373 is a new cardioregulatory hormone and that the removal of R373 represents a critical switch for turning "off" its cardioregulatory activity. [ABSTRACT FROM AUTHOR]

Lymph propulsion was, however, re-established in freely moving CavKO mice, suggesting that CavKO mice lacked intrinsic contractility typically seen in collecting lymphatic vessels. Our knowledge on lymphatic vessel function is lagging that of blood vessels. [Extracted from the article]

There was a significant reduction in SP 15 sp N-labeled muscle NO SB 3 sb SP - sp from pre- to post-exercise which has the important implication that the nitrate that accumulated in skeletal muscle following the dietary nitrate supplementation was utilized during the exercise bout. 15N-labeled dietary nitrate supplementation increases human skeletal muscle nitrate concentration and improves muscle torque production The biochemical background and physiological mechanism behind the fascinating effects of dietary nitrate supplementation is that nitric oxide (NO) can be formed nonenzymatically in the nitrate-nitrite-nitric oxide pathway via nitrite reduction. [Extracted from the article]

Abstract: The current guidelines following an acute coronary syndrome recommend dual‐antiplatelet therapy (DAPT) (aspirin plus a P2Y12 antagonist) alongside lifestyle modifications, including more regular physical activity. It is currently unknown whether regular exercise affects the pharmacology of DAPT. Aim: To explore how exercise‐induced improvements in vascular and platelet function affect the efficacy of DAPT, in a cross‐sectional study of men with different physical activity levels (training status). Methods: A total of 42 healthy, normal‐weight, middle‐aged men were divided into 3 groups: untrained, moderately trained and well‐trained. Their platelet reactivity (agonist‐induced % aggregation) was investigated in platelet‐rich plasma at rest and after inhibition with aspirin and ticagrelor and/or prostacyclin and nitric oxide added to the blood in vitro, and after physiological tests of vascular function; passive movement of the leg, flow‐mediated dilation and one‐leg knee‐extensor exercise. Vascular function of the femoral artery (changes in arterial blood flow) was assessed by ultrasound Doppler. Results: Platelets from the well‐trained subjects had lower basal reactivity, a higher sensitivity to the anti‐aggregatory effects of prostacyclin and were more potently inhibited by DAPT compared to the untrained subjects. The moderately trained and well‐trained subjects had a superior vascular function compared to untrained subjects, and their platelets were more inhibited by the passive movement, flow‐mediated dilation and one‐leg knee‐extensor exercise. Discussion: A habitually active lifestyle leads to an increased platelet sensitivity to pharmacological and physiological platelet inhibitors. We suggest that physical activity habits (training status) should be considered when personalizing and optimizing antithrombotic treatment strategies. [ABSTRACT FROM AUTHOR]

Aim The migrating motor complex ( MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide ( NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl- l-arginine ( l- NMMA) in combination with muscarinic receptor antagonist atropine and 5- HT3 receptor antagonist ondansetron. Methods Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase ( NOS) inhibitor l- NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l- NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results l- NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l- NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l- NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by l- NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion Nitric oxide suppresses phase III of MMC independent of muscarinic and 5- HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5- HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5- HT3-ergic mechanisms. [ABSTRACT FROM AUTHOR]

Aim Extracellular nucleotides activate cell-surface purinergic ( P2) receptors, contribute to the local regulation of vascular tone and play important roles in pathophysiological states. However, little is known about the vasodilator effects of P2 Y1-receptor activation in diabetic states. We hypothesized that in a model of established type 1 diabetes, long-term streptozotocin ( STZ)-induced diabetic rats, the arterial relaxation elicited by a P2 Y1-receptor agonist would be impaired. Methods Relaxations to adenosine 5′-diphosphate sodium salt ( ADP), 2- Me SADP (selective P2 Y1-receptor agonist) and adenosine 5′-triphosphate disodium salt ( ATP) were examined in superior mesenteric artery rings from long-term STZ-induced diabetic rats (at 50-57 weeks after STZ injection). ADP-stimulated nitric oxide ( NO) production in the superior mesenteric artery was assessed by measuring the levels of NO metabolites. Mesenteric artery expressions of P2 Y1 receptor, and ADP-stimulated levels of phosphorylated endothelial NO synthase (e NOS) (at Ser1177 and at Thr495) and e NOS were detected by Western blotting. Results Arteries from diabetic rats exhibited (vs. those from age-matched control rats): (i) reduced ADP-induced relaxation, which was partly or completely inhibited by endothelial denudation, by NOS inhibitor treatment and by a selective P2 Y1-receptor antagonist, (ii) reduced 2- Me SADP-induced relaxation, (iii) reduced ADP-stimulated release of NO metabolites and (iv) impaired ADP-induced stimulation of e NOS activity (as evidenced by reduced the fold increase in e NOS phosphorylation at Ser1177 with no difference in fold increase in e NOS phosphorylation at Thr495). The protein expression of P2 Y1 receptor did not differ between diabetic and control arteries. Conclusions These results suggest that P2 Y1-receptor-mediated vasodilatation is impaired in superior mesenteric arteries from long-term type 1 diabetic rats. This impairment is because of reduced P2 Y1-receptor-mediated NO signalling, rather than to reduced P2 Y1-receptor expression. [ABSTRACT FROM AUTHOR]

Aim It is known that garlic has antioxidative and anti-inflammatory properties. Aged red garlic ( ARG), a novel aged garlic formulation, has higher antioxidant effects than fresh raw garlic. This study was performed to examine the anti-inflammatory effects of ARG extract ( ARGE). Methods The anti-inflammatory effects of ARGE were evaluated in the lipopolysaccharide ( LPS)-treated Raw 264.7 macrophages and acute lung inflammatory mice. NO production was determined by the Griess method, and iNOS, HO-1 and COX-2 expressions were measured using Western blot analysis. Histology and inflammation extent of lung were analysed using haematoxylin-eosin staining and immunohistochemistry. Results ARGE treatment markedly reduced LPS-induced nitrite production in RAW 264.7 macrophages and reduced inducible nitric oxide synthase ( iNOS) expression. Treatment of cells with ARGE led to a significant increase in haeme oxygenase-1 ( HO-1) protein expression, which was mediated by stimulating the expression of nuclear factor erythroid 2-related factor 2 ( Nrf2). Treatment with zinc protoporphyrin, a selective inhibitor of HO-1, significantly reversed the ARGE-mediated inhibition of nitrite production ( P < 0.05). In LPS-induced inflammatory mice, ARGE treatment down-regulated iNOS and COX-2 expressions, while it up-regulated HO-1 expression. Conclusion These results show that ARGE reduces LPS-induced nitric oxide production in RAW 264.7 macrophages through HO-1 induction and suggest that ARGE may have potential effects on prevention and treatment of acute inflammatory lung injury. [ABSTRACT FROM AUTHOR]

The article introduces a paper about the role of endogenous nitric oxide (NO) in pulmonary embolism, that was published within the issue. Here, the researchers found out that the general inhibition of NO synthases is fatal when combined with pulmonary embolism, but selective inhibition of inducible NO synthase by aminoguanidine results to favorable effects on pulmonary haemodynamics.

Aim: Fructose intake has increased concurrent with sugar intake and this increase has been implicated in contributing to the development of metabolic syndrome risk factors. Recent evidence suggests a role for uric acid (UA) as a potential mediator via suppression of nitric oxide (NO) bioavailability. The aim of this study was to explore this hypothesis by measuring changes in UA concentration and systemic NO bioavailability as well as endothelial function in response to acute ingestion of a glucose-fructose beverage. Methods: Ten young (26.80 ± 4.80 years), non-obese (body mass index: 25.1 ± 2.55 kg m−2; percent body fat: 13.5 ± 6.9%) male subjects ingested either a glucose (100 g dextrose in 300 mL) or isocaloric glucose-fructose (glucose : fructose; 45 : 55 g in 300 mL) beverage. Blood was sampled pre- and every 15-min post-ingestion per 90 min and assayed for glucose, lactate, fructose, total nitrate/nitrate, UA and blood lipids. Forearm blood flow and pulse-wave velocity were recorded prior to and at 30 and 45 min time intervals post-ingestion, respectively, while heart rate, systolic and diastolic blood pressure were recorded every 15 min. Results: The glucose-fructose ingestion was associated with a significant ( P < 0.05) increase in plasma lactate concentration and altered free fatty acid levels when compared with glucose-only ingestion. However, UA was not significantly different ( P = 0.08) between conditions (AUC: −1018 ± 1675 vs. 2171 ± 1270 μmol L−1 per 90 min for glucose and glucose-fructose conditions respectively). Consequently, no significant ( P < 0.05) difference in endothelial function or systemic NO bioavailability was observed. Conclusion: Acute consumption of a fructose-containing beverage was not associated with significantly altered UA concentration, endothelial function or systemic NO bioavailability. [ABSTRACT FROM AUTHOR]

Aim: This study was performed to delineate the kinin (receptor)-dependent pathways in the Indian red scorpion ( Mesobuthus tamulus; MBT) venom-induced pulmonary oedema as well as the augmentation of cardio-pulmonary reflexes evoked by phenyldiguanide (PDG). Methods: In urethane-anaesthetized adult rats, the effect of venom on the PDG reflex responses (blood pressure, heart rate and respiration rate) and the pulmonary water content was ascertained using various antagonists(des- Arg, B1 receptor antagonist; Hoe 140, B2 receptor antagonist; Nω-nitro-l-arginine methyl ester (l-NAME), nitric oxide (NO) synthase inhibitor; methylene blue, soluble guanylate cyclase inhibitor; and glibenclamide, K+ATP channel blocker). The effect of phosphodiesterase V inhibitor (sildenafil citrate) on the reflex response and the pulmonary water content was also examined and compared with venom-induced responses. Results: Intravenous injection of PDG (10 μg kg−1) evoked apnoea, bradycardia and hypotension lasting >60 s. Exposure to MBT venom (100 μg kg−1) for 30 min augmented the PDG reflex responses by two times and increased the pulmonary water content, significantly. Hoe 140 blocked the venom-induced responses (augmentation of PDG reflex and increased pulmonary water content) whereas des-Arg did not.l-NAME, methylene blue or glibenclamide also blocked the venom-induced responses. Furthermore, sildenafil citrate (that increases cGMP levels) produced augmentation of PDG reflex response and increased the pulmonary water content as seen with venom. Conclusion: The results indicate that venom-induced responses involve B2 kinin receptors via the NO-dependent guanylate cyclase-cGMP pathway involving K+ATP channels. [ABSTRACT FROM AUTHOR]

Caveolae are omega-shaped membrane invaginations present in essentially all cell types in the cardiovascular system, and numerous functions have been ascribed to these structures. Caveolae formation depends on caveolins, cholesterol and polymerase I and transcript release factor-Cavin (PTRF-Cavin). The current review summarizes and critically discusses the cardiovascular phenotypes reported in caveolin-1-deficient mice. Major changes in the structure and function of heart, lung and blood vessels have been documented, suggesting that caveolae play a critical role at the interface between blood and surrounding tissue. According to an emerging paradigm, many of these changes are secondary to uncoupling of endothelial nitric oxide synthase. Thus, nitric oxide synthase not only synthesizes more nitric oxide in the absence of caveolin-1, but also more superoxide with potential pathogenic consequences. It is further argued that the vasodilating drive from increased nitric oxide production in caveolin-1-deficient mice is balanced by changes in the vascular media that favour increased dynamic resistance regulation. Harnessing the therapeutic opportunities buried in caveolae, while challenging, could expand the arsenal of treatment options in cancer, lung disease and atherosclerosis. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a major cause of death and morbidity. Connexin 43 (Cx43) content is reduced in the failing myocardium, but regulating factors have not been identified. In HF, inducible nitric oxide synthase (iNOS)-induced high levels of nitric oxide (NO) cause apoptosis and cardiac dysfunction. However, a direct iNOS–Cx43 link has not been demonstrated. We investigated this relationship in mice after myocardial infarction. Methods: Effects of myocardial infarction were evaluated 2 weeks after coronary artery ligation in wild-type C57BL/6 (WT) and iNOS−/− knockout mice. Myocardial Cx43 and Cx45 content were assessed by immunofluorescence confocal imaging and western blotting. Cardiac function was evaluated in anaesthetized mice using a micro pressure-tipped catheter inserted into the left ventricle. Results: Despite similar infarct size, deficiency in iNOS resulted in significantly lower plasma nitrate/nitrite levels, better haemodynamic performance and lower mortality 2 weeks after coronary ligation. Myocardial Cx43, but not Cx45, content was lower in WT mice following ligation. The reduction in Cx43 was less in iNOS−/− compared with WT mice. To assess the direct effect of NO on Cx43 expression, cultured neonatal mouse cardiomyocytes were employed. Incubation with the NO donor, S-nitroso- N-acetylpenicillamine, elicited a dose-dependent decrease in Cx43 content in cultured neonatal cardiomyocytes. Conclusions: Increased NO production from iNOS depressed cardiac performance and contributed to the decreased myocardial Cx43 content 2 weeks after myocardial infarction. [ABSTRACT FROM AUTHOR]

Aim: Hyaluronan (HA) is involved in renomedullary water handling through its water-binding capacity. This study addressed the effect of hormones involved in regulating fluid-electrolyte homeostasis on renomedullary HA content in vivo and in vitro. Methods: The kidneys from rats treated withl-NAME, indomethacin, vasopressin (AVP) or methylprednisolone (MP) during euvolaemia or water loading were analysed for HA by RIA, ELISA and histochemical staining. HA was measured in renomedullary interstitial cells treated with AVP, angiotensin II (Ang II) or a combination of AVP and Ang II. Results: Baseline renal cortical and medullary HA content was unaffected by 2 h of intravenous treatment withl-NAME (NOS inhibitor) or indomethacin (cyclo-oxygenase inhibitor), whereas AVP reduced medullary HA by 33%. During 2 h of acute water loading, diuresis was accompanied by an increase in renomedullary HA (+45%), but cortical HA was unaffected. In bothl-NAME- and indomethacin-treated animals, the water loading-induced increase in renomedullary HA was absent, indicating involvement of NO and prostaglandins. After 7 days of MP treatment, medullary HA was reduced by 40%, but the water loading-induced elevation in HA remained. In cultured renomedullary interstitial cells, AVP reduced the HA content in the supernatant by 63%, and simultaneous treatment with Ang II reduced the HA content even further (95%). Conclusion: AVP reduces HA content, and NO and prostaglandins are needed for the increase in HA during water loading. [ABSTRACT FROM AUTHOR]

Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt-sensitive hypertension. Methods: PUUO was created in 3-week-old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated. Results: All hydronephrotic animals developed salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes. Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt-sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before. [ABSTRACT FROM AUTHOR]

Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unravelled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signalling pathway and genetic variants. It is speculated that hypertension‐induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction in sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signalling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time. [ABSTRACT FROM AUTHOR]

The article discusses the effects of microvascular oxygen tensions on nitric oxide availability. The determination of microvascular PO2 by the dynamic balance between muscle oxygen consumption and delivery is offered. It also discusses how microvascular PO2 showed clear responses to nitric oxide availability, which may have important implications in health and disease.