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Ethnopharmacological Relevance: Nigella sativa L. seed has been widely used in traditional medicine for the treatment of diabetes. The major reason for vascular complications in diabetic patients is endothelial dysfunction. However, the impact of N. sativa seed on endothelial dysfunction in diabetes remains unclear., Aim of the Study: This study was conducted to evaluate the effect of the hydroalcoholic extract of N. sativa seed on eNOS, VCAM-1, and LOX-1 genes expression and the vasoreactivity of aortic rings to acetylcholine (Ach) in streptozotocin (STZ)-induced diabetic rat., Materials and Methods: Treated rats received N. sativa seed extract (100, 200, and 400 mg/kg) daily by gavage for 6 weeks. The fasting blood glucose and lipids were measured and atherogenic index of plasma (AIP) was calculated. The endothelium-dependent vasoreactivity responses of isolated aortic rings were evaluated in the presence of cumulative concentrations of Ach (10 -8 -10 -5 M). eNOS, VCAM-1, and LOX-1 genes expression in aortic tissue was assessed by using real time polymerase chain reaction (PCR)., Results: Male diabetic Wistar rats treated with N. sativa seed extract for six weeks reduced serum glucose and lipids and improved AIP. The vasorelaxant responses of aortic rings to Ach were markedly improved. N. sativa seed significantly increased eNOS in mRNA expression level and function, while it decreased VCAM-1 and LOX-1 expressions in vascular cells of aortic tissue which assessed only in mRNA level., Conclusions: The results of this study showed that N. sativa seed more likely, has antidiabetic and antihyperlipidemic properties and improved vasoreactivity, endothelial dysfunction, and vascular inflammation in diabetic rats' aorta., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tiliacorinine 12'-O-acetate is a modified analog of Tiliacorinine, a major compound in Tiliacora triandra. The present study explored the vasorelaxation property of tiliacorinine 12'-O-acetate and its mechanism in isolated rat aorta using the organ bath technique. Tiliacorinine 12'-O-acetate exhibited concentration-dependent (10 -15 -10 -3.5 M) vasorelaxation in endothelium-intact rings (E max  = 93.53 ± 2.79%) and endothelium-denuded rings (E max  = 74.31 ± 5.09%). The effects of tiliacorinine 12'-O-acetate were attenuated by pre-incubation with N(ω)-nitro-l-arginine methyl ester (L-NAME, endothelium nitric oxide synthase inhibitor) (100 μM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, soluble quanylylcyclase inhibitor) (1 μM), and 4-aminopyridine (1 mM, K v channel blocker). However, this effect was not impacted by indomethacin (10 μM, cyclooxygenase inhibitor), tetraethylammonium (5 mM, K ca channel blocker), barium chloride (1 mM, K IR channel blocker), or glibenclamide (10 μM, K ATP channel blocker). Moreover, pretreatment with tiliacorinine 12'-O-acetate reduced the effect of L-NAME (100 μM) on acetylcholine-induced vasorelaxation. Tiliacorinine 12'-O-acetate showed inhibitory effects on CaCl 2 -induced contracted rings and reduced the contraction induced by phenylephrine (10 μM) and caffeine (20 mM) in a Ca 2+ -free solution. The results of this study suggest that tiliacorinine 12'-O-acetate induced endothelium-dependent vasorelaxation through the eNOS/NO/sGC pathway, and also induced endothelium independent vasorelaxation involving the modulation of sGC activity, K v channels, Ca 2+ influx through Ca 2+ channels and intracellular Ca 2+ release. The data concerning the benefits of tiliacorinine 12'-O-acetate might be further investigated for the application of tiliacorinine 12'-O-acetate as an antihypertensive compound., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the weakening of the vascular walls and the progressive dilation of the abdominal aorta. Nicotine, a primary component of cigarette smoke, is associated with AAA development and rupture. Nicotine induces AAA development by weakening vascular walls. However, little is known about preventive methods using functional food factors for nicotine-induced vascular destruction. Sesamin and sesamolin are functional food factors that are fat-soluble lignans found in Sesamum indicum seeds. Previous reports indicated that sesamin and sesamolin have anti-oxidative and anti-inflammatory effects. In this study, we evaluated the effects of sesamin and sesamolin-rich sesame extract on the weakening of vascular walls in nicotine-administered mice. Sesame extract attenuated the degradation of collagen and elastin fibers caused by nicotine. In addition, sesame extract decreased the area positive for matrix metalloproteinase 12 (MMP-12) and oxidative stress in the vascular walls. These results suggest that sesame extract may decrease the weakening of vascular walls by suppressing the nicotine-induced degradation of collagen and elastin fibers. Sesame extract may be effective in preventing AAA development by decreasing both, MMP-12 expression and oxidative stress in vascular walls.

The cyclitol bornesitol is the main constituent of the leaves from the antihypertensive medicinal plant Hancornia speciosa. This study aimed to investigate the ability of bornesitol to reduce blood pressure and its mechanism of action. Normotensive Wistar rats were divided into control group and bornesitol groups treated intravenously with bornesitol (0.1, 1.0 and 3.0 mg/kg). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded in non-anesthetized awake animals. Nitric oxide (NO) and angiotensin-converting enzyme (ACE) were measured in plasma by using colorimetric methods. Vascular reactivity study was performed in rat aorta rings and the involvement of nitric oxide synthase (NOS), calcium-calmodulin complex and phosphatidylinositol-3-kinase (PI3K)/Akt pathway in the vasodilator effect was investigated. Administration of bornesitol significantly reduced the SBP, increased the plasmatic level of nitrite, and decreased ACE activity in normotensive rats. In the rat aorta, bornesitol induced endothelium-dependent vasodilatation, which was abolished by NOS blockade. While calcium-calmodulin complex inhibition decreased the vasodilator effect of bornesitol, the inhibition of PI3K/Akt pathway did not alter it. Bornesitol reduced the blood pressure by a mechanism involving an increased production or bioavailability of NO, inhibition of ACE, and by an endothelium- and NO-dependent vasodilator effect. The present results support the use of bornesitol as an active marker for the cardiovascular activity of Hancornia speciosa.

An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.

This study was designed to characterize the pharmacological profile of DS37001789, which is a structurally novel piperazine derivative that acts as urotensin II (U-II) receptor antagonist. DS37001789 inhibited [I]-U-II binding to human GPR14, U-II receptor, with an IC50 value 0.9 nM. Its potency was superior to that of ACT-058362, a nonpeptide U-II receptor antagonist whose IC50 was 120 nM. Human U-II-induced vascular contraction was blocked by DS37001789. The dose-response curve of DS37001789 in rats and monkeys did not show species differences, and it shifted to the right without any effects on the maximum vascular response. Moreover, orally administered DS37001789 dose-dependently prevented human U-II-induced blood pressure elevation in mice, and this effect was significant at dose and higher dose (30 and 100 mg/kg), and its potency was superior to that of ACT-058362 (100 mg/kg). These results suggest that DS37001789 is a highly potent U-II receptor antagonist both in vitro and in vivo, with no marked species difference. DS37001789 would be a useful tool to clarify the physiological roles of U-II/GPR14 system. In addition, it can serve as a novel therapeutic agent for diseases in which the U-II/GPR14 system is upregulated, such as hypertension, heart failure, renal dysfunction, and diabetes.

Orthovanadate (OVA), a protein tyrosine phosphatase inhibitor, induces contraction in endothelium-denuded mouse thoracic aortas. OVA-induced contraction was significantly (vs. control rings) suppressed by Rho kinase (Y-27632, 10 µM), extracellular signal-regulated kinase 1 and 2 (Erk1/2, FR180204, 10 µM), Erk1/2 kinase (MEK, PD98059, 10 µM), epidermal growth factor receptor (EGFR, AG1478, 10 µM), and Src inhibitors, and was partially suppressed by c-Jun N-terminal kinase (JNK, AS601245, 10 µM) and p38 (SB203580, 10 µM) inhibitors. However, a myosin light chain kinase inhibitor (ML-7, 10 µM) and a metalloproteinase inhibitor (TAPI-0, 10 µM) had no effect on OVA-induced contraction in mouse thoracic aortas. Phosphorylation of myosin phosphatase target subunit 1 (MYPT1) was abolished by inhibitors of Src, EGFR, MEK, Erk1/2, and Rho kinase, but not by inhibitors of JNK and p38. Erk1/2 phosphorylation by OVA was blocked by inhibitors of EGFR, Src, MEK, and Erk1/2, but not by Rho kinase inhibition. Src phosphorylation at Tyr-416 was abrogated by only Src inhibitor. EGFR phosphorylation at Tyr-1173 was suppressed by a Src inhibitor. These findings suggest that OVA induces contraction via activation of Src, EGFR, MEK, Erk1/2, and Rho kinase, leading to inactivation of myosin light chain phosphatase via MYPT1 phosphorylation.

Previous studies have shown that the anti-contractile effect of the perivascular adipose tissue (PVAT) is attenuated in pregnancy. In the present investigation, we have examined the possibility that this loss of anti-contractile effect could be due to changes in calcium mobilization. PVAT exerted anti-contractile effect against 5-hydroxytryptamine (5-HT)-induced contractions of aorta segments from pregnant and non-pregnant rats and this anti-contractile effect was attenuated in segments from pregnant rats. Nifedipine (10-6 mol/L), an inhibitor of L-type dihydropyridine calcium channels, significantly reduced 5-HT-induced contraction of aorta segments from non-pregnant and pregnant rats with and without PVAT. The inhibitory effect of nifedipine against 5-HT-induced contractions was attenuated in PVAT-free aorta segments from pregnant rats. However, while PVAT reduced the effectiveness of nifedipine in aorta segments from non-pregnant rats, it partially restored the inhibitory effect of nifedipine in aorta segments from pregnant rats. Inhibitors of calcium sensitization, Y-27632 (10-6 mol/L) and GF 109203X (10-6 mol/L), significantly reduced 5-HT-induced contractions of PVAT-free aorta segments from non-pregnant and pregnant rats. Both inhibitors, however, were less effective in aorta segments from pregnant rats. The presence of PVAT reduced the effectiveness of Y-27632 and GF 109203X in aorta segments from pregnant and non-pregnant rats. Protein expression of Rho-associated protein kinase (ROCK) I and II was detected in aorta segments and PVAT from pregnant and non-pregnant rats. There was a reduction in the expression of both isoforms in aorta segments but not PVAT from pregnant rats. In addition, there was no significant difference in the expression of ROCK-I and ROCK-II in PVAT from pregnant and non-pregnant rats. We concluded that the loss of anti-contractile effect of PVAT in aorta segments from pregnant rats could be due to increased influx of extracellular calcium through nifedipine-sensitive dihydropyridine channels., (© 2019 S. Karger AG, Basel.)

Numerous studies have demonstrated the impaired cardiovascular reactivity in cholestasis patients and bile duct ligated animals. However, the underlying mechanism remains uncertain. Transient receptor potential cation V4 (TRPV4) channels are reported to be naturally expressed in the cardiovascular system, especially on endothelial cells. However, the role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular reactivity is poorly established. In this study, we first determined that bile acids elicited endothelium-dependent vasoconstrictor hypo-activity via TRPV4 channels, which further activated cyclooxygenase 2 (COX2). Myography results demonstrated that the vascular contractile response was attenuated in BDL rats when exposed to 60 mmol/L KCl. Real time PCR and western blotting results showed that bile duct ligation (BDL) induced a time-dependent increase in TRPV4 expression levels. In addition, bile acids upregulated the expression of TRPV4 protein, which proved to be located on the cell surface of endothelial cells, and induced intracellular Ca 2+ events. The relaxation response was increased while the contractile response was decreased in BDL rats, and those effects were reversed by a TRPV4 inhibitor (HC067047). Contractions induced by norepinephrine were primarily inhibited by the COX2 inhibitor, but not the NOS inhibitor, and the expression of COX2 was downregulated after TRPV4 inhibition. These data indicated that TRPV4/COX2 pathways in the endothelium are involved in vasoconstrictor hypo-activity. Our current results suggested that the TRPV4 pathway is involved in the regulation of bile acids in vasoconstrictor hypo-activity in bile duct ligation rats., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Statins are widely used in the treatment of hypercholesterolemia. Studies have demonstrated that statins could maintain vascular contractile function through inhibiting the transformation of vascular smooth muscle cells (VSMCs) from the contractile phenotype to the synthetic phenotype. However, the underlying mechanisms have not been fully elucidated. The effect of atorvastatin on the thoracic aorta of Sprague-Dawley rats cultured in serum-free conditions in vitro was evaluated. Aortic constriction was induced by high potassium, phenylephrine, and CaCl 2 . The protein expression levels of α 1 adrenoceptor; inositol 1,4,5-trisphosphate (IP 3 ) receptor; protein kinase C δ (PKC δ ); stromal interaction molecule 1 (STIM1); high-voltage activated dihydropyridine-sensitive (L type, Cav1.2) channels; and two contractile phenotype marker proteins [α-smooth muscle actin (α-SMA) and myosin (SM-MHC)] were determined by western blotting. Compared with the fresh control, the constriction of rat aorta was impaired after culture in serum-free medium for 24 h. The impaired contraction of cultured aortas was mediated by Cav1.2 and store-operated Ca 2+ (SOC) channel, which could be improved by atorvastatin at 20 μM. The protein expression levels of α 1 adrenoceptor, IP 3 receptor, PKC δ , STIM1, Cav1.2, α-SMA, and SM-MHC in the aortas cultured in serum-free conditions were decreased significantly. Atorvastatin partially prevented the reduction in the contractility and the downregulation of these proteins in cultured aortas. The transformation of the VSMC phenotype is associated with the vasoconstriction dysfunction of cultured aortas. Atorvastatin may protect vascular function by modulating calcium signaling pathways.

Epidemiological evidence supports a reduced prevalence of Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) in patients with Diabetes (DM). The mechanisms underlying this negative association are unknown. Some studies support that hyperglycemia has effects on the Extracellular Matrix (ECM), resulting in collagen cross-links and altered proteolytic activity, which ultimately counteracts aneurysm formation. However, recent experimental research indicates that incretin- based anti-diabetic therapy and Glucagon-Like Peptide-1 (GLP-1) may reduce the formation of TAA. GLP-1 is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signaling exerts numerous pleiotropic effects on various tissues, including protective effects on the myocardium and vascular endothelium. Recent studies also report protective effects of GLP-1 based therapy on the formation of aneurysms in animal models and direct effects of GLP-1 signaling on the molecular mechanisms suggested to influence TAA formation, including inflammation, proteolytic activity and collagen composition. In this narrative review, we present the available evidence for effects of GLP-1 on experimental aneurysm development and discuss the potential role of GLP-1 in aneurysm formation based on available data from pre-clinical and clinical studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Sophorolipids (SLs) are a group of surface-active glycolipids produced by a type of nonpathogenic yeast Candida bombicola in the presence of vegetable oil through fermentation technology. SLs have shown antitumor activity; however, the mechanism of action underlying the anticancer activity of SLs is poorly understood. This work evaluated the anticancer activity of SLs fermented from palm oil by exploring its antiangiogenic activity., Materials and Methods: The SLs that were fermented and further characterized for their biochemical activities. Cytotoxicity study was performed to assess cytostatic properties. A series of in vitro and ex vivo angiogenesis assay was also carried out. The relative fold change in the expression of p53 mRNA by SLs was also studied., Results: Altogether, the data show that SLs derived from palm oil fermentation process inhibited neovascularization in the ex vivo tissue segments and also the endothelial cell proliferation between 50% and 65% inhibition as a whole. The palm oil derived SLs also caused downregulation of the suppression level of vascular endothelial growth factor and also upregulate the p53 mRNA level. The analytical studies revealed the presence of high amount of phenolic compounds but with relatively weak antioxidant activity. The gas chromatography-mass spectrometry studies revealed abundant amount of palmitic and oleic acid, the latter an established antiangiogenic agent, and the former being proangiogenic., Conclusion: Therefore, it can be concluded from this study that SLs derived from fermented palm oil have potent antiangiogenic activity which may be attributed by its oleic acid component., Competing Interests: There are no conflicts of interest.

Seven new isoprenyl phenolic ethers, namely fimbriethers A‒G (1‒7), were isolated from the fermented broth of the termite nest-derived medicinal fungus Xylaria fimbriata YMJ491. Their structures were determined by spectroscopic data analysis and compared with those reported. The effects of all the isolates at a concentration of 100 μM on the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells were evaluated, and all of them exhibited NO production inhibitory activity with E max values ranging from 4.6 ± 2.0% to 49.7 ± 0.5% without significant cytotoxicity. In addition, these seven compounds did not alter phenylephrine-induced vasocontraction in isolated intact thoracic aortic rings from C57BL/6J mouse, indicating 1‒7 were not involved in the regulation of endothelial NOS-mediated NO production., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

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

The Lippia alba (Mill.) N.E. Brown (Verbenaceae) species popularly known as lemon balm has sedative, analgesic and spasmolytic properties. This study aimed to evaluate the vasorelaxant effect of the L. alba essential oil (EOLa) and its major constituent, citral, rat on aorta. Isometric muscle contraction were induced by potassium (K 60 mM) or phenylephrine (PHE, 0.1 μM) in isolated aortic rings. EOLa and citral promoted a smooth muscle relaxant action, which was potentiated by the presence of the endothelium; PHE-induced contractions (0.1 μM) in aorta with endothelium, had EC 50 values of 352.73 ± 19.39 μg/mL and 99.34 ± 7.2 μg/mL for EOLa and citral, respectively. In the presence of a nitric oxide synthase inhibitor, L-NAME, the EC 50 values were 654.19 ± 10.46 μg/mL and 601.66 ± 10.922 μg/mL for EOLa and citral, respectively. EOLa and citral dose-dependently relaxed contractions induced by BAY-K 8644, a calcium channel agonist, and by Phorbol 12,13-dibutyrate an activator of protein kinase C. EOLa and citral produced a vasorelaxant effect in isolated aorta which was potentiated by the presence of endothelium. In summary, EOLa and citral, probably using several mechanisms of action, relaxed aortic smooth muscle with maximal pharmacologic efficacy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Antihypertensive pharmacological treatments focus on the use of angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists, and beta-blockers as single and combined treatments. The effect of single treatments on the mRNA expression of some components of the renin-angiotensin system has been studied, but not the effect of combined treatments. This study determined the expression of the AT1, AT2, B1, and B2 receptors and of the enzymes ACE and ACE2 in hypertensive rats treated with captopril-propranolol or losartan-propranolol. Methods: The mRNA expression of the receptors and enzymes was determined by reverse transcription-quantitative polymerase chain reaction in the aorta of spontaneously hypertensive rats under different treatments. Results: Rats under combined treatments showed a decrease in the expression of AT1 and ACE, and an increase in the expression of the B1 receptor (captopril + propranolol group: 0.43 ± 0.046, 2.243 ± 0.269, 3.356 ± 0.418; Group: losartan + propranolol: 0.727 ± 0.071, 0.852 ± 0.102, 1.277 ± 0.131 compared to the spontaneously hypertensive group: 1 ± 0.212, 1 ± 0.192, 1 ± 0.214). This decrease in the expression of ACE and AT1 suggests a reduction in the expression of Ang II that could be related to a lower response to this vasoconstrictor. An increase in the expression of B1 would improve vasodilation, which would be a beneficial effect of combined therapies for hypertension.

Context: Rumex acetosa L. (Polygonaceae) is well known in traditional medicine for its therapeutic efficacy as an antihypertensive., Objective: The study investigates antihypertensive potential of crude methanol extract (Ra.Cr) and fractions of Rumex acetosa in normotensive and hypertensive rat models and probes the underlying vascular mechanisms., Materials and Methods: Ra.Cr and its fractions were tested in vivo on normotensive and hypertensive Sprague-Dawley rats under anaesthesia for blood pressure lowering effect. In vitro experiments on rat and Oryctolagus cuniculus rabbit aortae were employed to probe the underlying vasorelaxant mechanism., Results: In normotensive rats under anaesthesia, Ra.Cr caused fall in MAP (40 mmHg) at 50 mg/kg with % fall of 27.88 ± 4.55. Among the fractions tested, aqueous fraction was more potent at the dose of 50 mg/kg with % fall of 45.63 ± 2.84. In hypertensive rats under similar conditions, extract and fractions showed antihypertensive effect at same doses while aqueous fraction being more potent, exhibited 68.53 ± 4.45% fall in MAP (70 mmHg). In isolated rat aortic rings precontracted with phenylephrine (PE), Ra.Cr and fractions induced endothelium-dependent vasorelaxation, which was partially blocked in presence of l-NAME, indomethacin and atropine. In isolated rabbit aortic rings pre-contracted with PE and K + -(80 mM), Ra.Cr induced vasorelaxation and shifted Ca 2+ concentration-response curves to the right and suppressed PE peak formation, similar to verapamil, in Ca 2+ -free medium., Discussion and Conclusions: The data indicate that l-NAME and atropine-sensitive endothelial-derived NO and COX enzyme inhibitors and Ca 2+ entry blocking-mediated vasodilator effect of the extract explain its antihypertensive potential.

Scope: The flavonoid quercetin reduces arterial blood pressure in animals and humans but the mechanisms remains elusive. The aim of this study was to test the activity of flavonoid microbial metabolites, which can participate on the final vasorelaxant effect., Methods and Results: Both ex vivo (isolated rat thoracic aorta and mesenteric artery) and in vivo (normotensive and spontaneously hypertensive rats) approaches were used in this study. 4-methylcatechol and 3,4-dihydroxyphenylacetic acid (DHPA) had greater vasorelaxant effects on mesenteric artery than 3-(3-hydroxyphenyl)propionic acid, the previously reported metabolite with vasorelaxant effect. In vivo testing confirmed their blood pressure decreasing effect given both as bolus and slow infusion. Their mechanism at molecular level was different., Conclusions: This study is the first to show that flavonoid metabolites DHPA and 4-methylcatechol decrease arterial blood pressure and hence a mixture of microbial metabolites formed in the gastrointestinal tract may be responsible for or contribute to the effect of orally ingested quercetin., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: Dihydromyricetin (DMY) has oxidation resistance, anti-inflammatory and free radical scavenging capabilities. The preventive effects of DMY for vascular hyporeactivity remain unclear., Objective: This study investigates the preventive effects of DMY in vascular hyporeactivity., Materials and Methods: The experimental sepsis was induced by transvenous administration of lipopolysaccharide (LPS) to Sprague-Dawley (SD) rats. DMY-treated rats received daily administration of DMY, 5 μg/kg dissolved in DMSO through the tail vein for 7 days. The invasive mean arterial pressure (MAP) of the caudal ventral artery was measured. Dose-response curves for norepinephrine (NE, doses from 10 -9 to 10 -6  M) were obtained in isolated thoracic aorta in a cumulative manner. The function of MaxiK and K ATP channels were investigated using whole-cell patch clamp recording. The Elisa was adopted to measure the serum concentration of NO, MDA, 3-NT, IL-1β and TNF-α., Results: The increased MAP in septic rats induced by vasopressor agents was smaller than that in control rats. However, the % of increased MAP induced by vasopressor agents was raised by DMY injection (NE: 20.4 ± 8.495 vs. 15.16 ± 5.195%; AVP: 14.05 ± 2.459 vs. 9.583 ± 2.982%, p < 0.05). The vascular hyporesponsiveness to NE (10 -6  M) in vitro. was increased by 51% in LPS + DMY group compared with that in LPS + Con group (2.74 ± 0.81 vs. 1.82 ± 0.92 g, p < 0.05). Charybdotoxin (a potent MaxiK channel blocker) and glibenclamide (a K ATP channel blocker) pretreatment, instead of 4-aminopyridine (4-AP) and BaCl 2 , could diminish the DMY-induced improvement of vasoconstrictor hyporeactivity (ChTX: 73.2 ± 11.8 vs. 71.8 ± 13.5%; Glib: 63.1 ± 12.5 vs. 58.1 ± 13.7%, p > 0.05). DMY blunted the highly sensitized MaxiK and K ATP channels of arterial smooth muscle cells isolated from the thoracic aorta of LPS rats. DMY decreased the serum level of NO, MDA, IL-1β and TNF-α, which had increased in LPS rats., Discussion and Conclusions: Our results indicate that DMY administration ameliorated the impaired contractility of the rat aorta in experimental sepsis. Such an effect is mediated by normalization of the over-excited MaxiK and K ATP , channels possibly via oxidative stress inhibition.

8-Oxo-9-dihydromakomakine is a tetracyclic indole alkaloid extracted from leaves of the Chilean tree Aristotelia chilensis . The present study investigated the effects of this alkaloid on vascular response in tissues isolated from aortic segments obtained from normotensive rats. Our results showed that 8-oxo-9-dihydromakomakine induced a dose-dependent relaxation of aortic rings pre-contracted with phenylephrine (PE; 10 -6 M). The vasorelaxation induced by 8-oxo-9-dihydromakomakine in rat aortic rings is independent of endothelium. The pre-incubation of aortic rings with 8-oxo-9-dehydromakomakine (10 -4 M) significantly reduced the contractile response to KCl ( p < 0.001) more than PE ( p < 0.05). The highest dose of 8-oxo-9-dehydromakomakine (10 -4 M) drastically reduced the contraction to KCl (6·10 -2 M), but after that, PE (10 -6 M) caused contraction ( p < 0.05) in the same aortic rings. The addition of 8-oxo-9-dihydromakomakine (10 -5 M) decreased the contractile response to tetraethylammonium (a voltage-dependent potassium channels blocker; TEA; 5 × 10 -3 M; p < 0.01) and BaCl₂ (a non-selective inward rectifier potassium channel blocker; 5 × 10 -3 M; p < 0.001) in rat aorta. 8-oxo-9-dihydromakomakine (10 -5 M) decreased the contractile response to PE in rat aorta in the presence or absence of ouabain (an inhibitor of Na,K-ATPase; 10 -3 M; p < 0.05). These results could indicate that 8-oxo-9-dihydromakomakine partially reduces plasma membrane depolarization-induced contraction. In aortic rings depolarized by PE, 8-oxo-9-dihydromakomakine inhibited the contraction induced by the influx of extracellular Ca 2+ in a Ca 2+ free solution ( p < 0.01). 8-oxo-9-dihydromakomakine reduced the contractile response to agonists of voltage-dependent calcium channels type L (Bay K6844; 10 -8 M; p < 0.01), likely decreasing the influx of extracellular Ca 2+ through the voltage-dependent calcium channels. This study provides the first qualitative analysis indicating that traditional folk medicine Aristotelia chilensis may be protective in the treatment of cardiovascular pathologies.

Slc29a1 encodes for equilibrative nucleoside transporter subtype 1 (ENT1), the primary mechanism of adenosine transfer across cell membranes. Previous studies showed that tissues isolated from Slc29a1-null mice are relatively resistant to injury caused by vascular ischemia-reperfusion. To determine if there are similar changes in the microvasculature, and investigate underlying mechanism, we examined aortas isolated from wildtype and Slc29a1-null mice. Aorta macrostructure and gene expression were examined histologically and by qPCR, respectively. Wire myography was used to assess the contractile properties of isolated thoracic aortic rings and their response to adenosine under both normoxic and hypoxic conditions. In vivo haemodynamic parameters were assessed using the tail-cuff method. Slc29a1-null mice had significantly (P<0.05) increased plasma adenosine (2.75-fold) and lower blood pressure (~15% ↓) than wild-type mice. Aortas from Slc29a1-null mice were stiffer with a smaller circumference (11% ↓), and had an enhanced contractile response to KCl and receptor-mediated stimuli. Blockade of ENT1 with nitrobenzylthioinosine significantly enhanced (by ~3.5-fold) the response of aorta from wild-type mice to phenylephrine, but had minimal effect on aortas from Slc29a1-null mice. Adenosine enhanced phenylephrine-mediated constriction in the wild-type tissue under both normoxic (11.7-fold) and hypoxic (3.6-fold) conditions, but had no effect on the Slc29a1-null aortic aorta. In conclusion, aortas from Slc29a1-null mice respond to hypoxic insult in a manner comparable to wild-type tissues that have been pharmacologically preconditioned with adenosine. These data also support a role for ENT1 in the regulation of the protective effects of adenosine on contractile function in elastic conduit arteries such as thoracic aorta., Competing Interests: The authors have declared that no competing interests exist.

We investigated whether resveratrol (RSV) can attenuate obesity and diabetes progression and improve diabetes-induced vascular dysfunction, and we attempted to delineate its underlying mechanisms. Male C57Bl/6 mice were administered a high-fat diet (HFD) for 17 weeks. Mice developed type 2 diabetes with increased body weight, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Oral gavage with RSV significantly reversed the symptoms induced by the HFD. Insulin sensitivity likewise improved after the RSV intervention in these mice. Phenylephrine-induced cremaster arteriolar constriction was impaired, whereas RSV treatment significantly mitigated the vessel responsiveness to phenylephrine. The obese diabetic mice exhibited increased leukocyte rolling, adhesion, and transmigration in the postcapillary venules of the cremaster muscle. By contrast, RSV treatment significantly attenuated HFD-induced extravasation. RSV significantly recovered phosphorylated Akt and eNOS expression in the thoracic aorta. In addition, activated adenosine monophosphate-activated protein kinase in the thoracic aorta was involved in the improvement of epithelial function after RSV intervention. RSV considerably upregulated the plasma NO level in HFD mice. Moreover, RSV-enhanced human umbilical vein endothelial cells healing through Sirt1/ER pathway may be involved in the prevention of leukocyte extravasation. Collectively, RSV attenuates diabetes-induced vascular dysfunction by activating Akt/eNOS/NO and Sirt1/ER pathway. Our mechanistic study provides a potential RSV-based therapeutic strategy against cardiovascular disease.

Danzhi jiangtang capsule (DJC) is mainly used to treat type 2 diabetes mellitus and vascular complication. Our aim was to investigate whether the protective effects of DJC by oral administration on high-fat diet (HFD) and palmitic acid-induced damages of endothelial cells are related to oxidative stress and endoplasmic reticulum (ER) stress. Male Sprague-Dawley rats were randomly divided into standard chow diet (SCD), HFD, HFD plus DJC-low dose (HFD + DJCL) and HFD plus DJC-high dose treatment groups (HFD + DJCH). The latter three groups were given HFD feeding for three months, then the HFD + DJCL and HFD + DJCH rats were treated with DJC (500 and 1000 mg/kg/day) via gavage for another two months respectively. Endothelium-dependent relaxations induced by acetylcholine were observed in isolated rat thoracic aortic ring preparation. Malondialdehyde (MDA), total-antioxidant capacity (T-AOC), superoxide dismutase (SOD), interleukin 1β (IL-1β), tumour necrosis factor α (TNFα), free fatty acids (FFA), endothelin-1 (ET-1) and nitric oxide (NO) levels in serum were assayed. The pathological changes, protein expression of endothelial NO synthase (eNOS), phosphorylated eNOS (p-eNOS) and ER stress-related genes in the thoracic aorta were measured. Human umbilical vein endothelial cells (HUVEC) were treated with serum-medicated DJC and then with palmitic acid to detect the reactive oxygen species (ROS) levels and C/EBP homologous protein (CHOP) distribution, expression of p-eNOS and ER stress-related genes. DJC therapy exhibited a potent antioxidant activity and effectively prevented the endothelial dysfunction (ED) manifested by promoting p-eNOS expression and enhancing NO release, decreasing lipid deposition (Oil-red O staining, CPT1b and ACC) and inflammation (IL-1β, TNFα, CD68 and p-JNK), alleviating oxidative and ER stress, and decreasing the apoptosis of endothelial cells (TUNEL, BCL-2 and BAX) induced by HFD and palmitic acid respectively. These findings suggest that the administration of DJC had endothelial protective effects against HFD-induced ED, inflammation and apoptosis by alleviating lipid deposition, oxidative and ER stress., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Formononetin (FMN) is an isoflavone that produces arterial vasodilation. However, the underlying molecular mechanisms are unclear., Purpose: The purpose of this study was to explore the vasorelaxant effect and the potential mechanism of FMN in vascular endothelium in isolated rat aorta., Methods: The thoracic aortas of Sprague Dawley rats were isolated to test the arterial reactivity in the presence of FMN with or without inhibitors. Bioinformatics analyses, including a Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and molecular docking methods, were performed to predict therapeutic targets responsible for the vascular protection produced by FMN. We used rat aortic endothelial cells (RAOECs) as an in vitro model to verify the potential mechanism through molecular biological analyses. The production of nitric oxide (NO) metabolites were evaluated via an NO assay kit according to the manufacturer's instruction. The mRNA expression of eNOS was analyzed by polymerase chain reaction, and the protein levels of PTEN, phosphorylated Akt, and eNOS were measured by Western blot., Results: We found that FMN dilated rat aortic rings in a concentration-dependent manner, which was reduced by endothelium denudation and eNOS inhibition. The bioinformatics analyses indicated that FMN activity was associated with the PI3K/PTEN/Akt signaling pathway. Molecular biological studies demonstrated that FMN significantly elevated the levels of NO and eNOS mRNA and markedly increased the protein expression of phosphorylated Akt and eNOS in RAOECs, and decreased PTEN compared with a dimethyl sulfoxide group., Conclusion: FMN performs vasorelaxation of the thoracic aorta through activating the PI3K/PTEN/Akt signaling pathway., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

To detect the structure‑activity associations of farrerol derivatives, the relaxation activity of farrerol derivatives was observed in isolated aortic rings pre‑contracted using phenylephrine in Sprague‑Dawley rats. All compounds tested in the present study produced a relaxation effect, which was significantly affected by the molecular structure. Using a collagen gel contraction assay, the present study further evaluated the inhibitiory effect of farrerol derivatives in a decreased collagen gel area, induced by Angiotensin II. The results indicated that farrerol derivatives could inhibit collagen contraction, and that the inhibitory effect was associated with the molecular structure of the compounds. Furthermore, the inhibitory strength of the different compounds was consistent with the results of vascular tension detection. The activity of the farrerol derivatives was closely associated with the molecular structure. The analysis indicated that an electron‑withdrawing substituent in the ortho position of the phenyl group (ring B) was crucial in order to observe improved vasorelaxation activity, whereas a hydroxyl or methoxy group was unfavorable. A para electron‑donating group was oberved to increase compound activity. In addition, when the B ring was heterocycle rather than a phenyl ring, the vasorelaxation ability was weakened.

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv ® , an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv ® is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of fruit and vegetables commonly consumed within the Mediterranean diet. A total of 21 Golden Syrian hamsters were divided into three groups. The standard group (STD) was fed a normolipidemic diet for 12 weeks, while the control group (CTRL) and Oleactiv ® goup (OLE) were fed a high-fat diet. After sacrifice, the aortic fatty streak area (AFSA), plasmatic total cholesterol (TC), high-density lipoproteins (HDL-C), non-HDL-C and triglycerides (TG), were assessed. The cholesterol efflux capacity (CEC) of hamster plasma was quantified using a radiolabeled technique in murine macrophages J774. OLE administration induced a significant reduction of AFSA (-69%, p < 0.0001). Hamsters of the OLE group showed a significant decrease of both non-HDL-C (-173 mmol/L, p < 0.05) and TG (-154 mmol/L, p < 0.05). Interestingly, OLE induced a significant increase of total CEC (+17,33%, p < 0,05). Oleactiv ® supplementation prevented atheroma development and had positive effects on the lipid profile of hypercholesterolemic hamsters. The increased CEC underlines the anti-atherosclerotic mechanism at the root of the atheroma reduction observed.

Ethnopharmacological Relevance: Eruca sativa Mill., (Brassicaceae) is a popular remedy for the treatment of hypertension in Pakistan. However, direct effect of the extract and its fractions on blood pressure and vascular tone are unknown., Aim of the Study: This investigation was aimed to explore the pharmacological base for the traditional use of E. sativa in hypertension., Materials and Methods: In-vivo blood pressure study was carried out using normotensive and high salt-induced hypertensive rats under anaesthesia. The cardiovascular mechanisms were explored using rat aorta and atria in-vitro. Preliminary phytochemical analysis, spectrophotometric detection of total phenols, flavonoids and HPLC analysis of crude extract were performed using quercetin and erucin as marker compounds., Results: Intravenous injection of crude extract induced a fall in mean arterial pressure (MAP) in both normotensive (max fall: 41.79 ± 1.55% mmHg) and hypertensive (max fall: 58.25 ± 0.91% mmHg) rats. Atropine (1 mg/kg) pretreatment attenuated this effect significantly (p < 0.001), suggesting the involvement of muscarinic receptor in its antihypertensive effect. Fractions also induced atropine-sensitive antihypertensive effect. Similarly, oral administration of crude and aqueous extracts resulted a fall in MAP in the hypertensive rats. In isolated rat aortic rings from normotensive rats, crude extract and fractions induced an endothelium-dependent relaxation. This relaxation was partially inhibited with L- NAME and atropine pretreatment and with denudation of aortic rings, indicating involvement of muscarinic receptor-linked nitric oxide (NO). In aorta from the hypertensive rats, crude extract and fractions induced endothelium-independent relaxation. This relaxation was not affected by pretreatment with L- NAME or atropine. Crude extract and fractions also suppressed phenylephrine contractions in Ca +2 free/EGTA medium. In isolated rat atrial preparations, crude extract and fractions induced negative inotropic and chronotropic effects with a positive inotropic effect by the n-hexane fraction, which were not affected with atropine pretreatment. Phytochemical screening and spectrophotometric analysis indicated the presence of phenols and flavonoids, whereas HPLC analysis of crude extract revealed the presence of quercetin (flavonoid) and erucin (isothiocyanate)., Conclusion: The results suggest that E. sativa is an antihypertensive remedy which is mainly due to its vasodilatory and partly cardiac effects. Muscarinic receptors-linked NO release and dual inhibitory effect on Ca +2 influx and release underlie the vasodilation. This finding provides pharmacological base to the traditional use of E. sativa in hypertension. The presence of quercetin and erucin further support this finding., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although Takayasu arteritis (TA) is rare as a form of chronic inflammatory arteritis, it is important that it is diagnosed early because the 10-year survival rate is only 84% to 87%. Many reported patients have been young women in East Asia. We report a case of a young woman who originally presented with unexplained pulmonary consolidation. Five years later, contrast-enhanced computed tomography (CT) imaging showed thickening of the walls of the aorta and its branches and of the main and right pulmonary artery (PA), and occlusion of the left subclavian and left PAs. A diagnosis of TA was made based on these CT findings. Patients with TA often have PA involvement, and this can be the initial site of arteritis. Therefore, TA should be included in the differential diagnosis of young women with unexplained pulmonary consolidation.

Objective- Vascular endothelial dysfunction is a key component of several major human diseases, but the molecular basis of this complex disorder has been difficult to determine in vivo. Previous attempts to identify key mediators of vascular endothelial dysfunction in experimental models have been limited by the lack of suitable methods for system-wide analyses of vascular bed biology. Here, we aimed to develop a novel method for investigating vascular endothelial dysfunction pathogenesis that enables system-wide analyses of molecular interactions between endothelial glycocalyx, endothelial cells, and smooth muscle cells in murine. Approach and Results- We developed a new technique using whole-body differential perfusion with increasing concentrations of detergent buffer to selectively solubilize distinct layers of vascular bed tissue in rodents. When combined with proteomics techniques, our novel approach of differential systemic decellularization in vivo enabled quantitative profiling of vascular beds throughout the body. Initial perfusion with phosphate buffer was used to obtain the endothelial glycocalyx, followed by subsequent extraction of endothelial cell components, and finally by smooth muscle cell constituents with increasing concentrations of detergent. Differential systemic decellularization in vivo has also been successfully applied to characterize molecular events in the vascular bed pathology of lipopolysaccharide-challenged mice. Conclusions- Together, these data indicate that differential systemic decellularization in vivo permits system-wide molecular characterization of vascular bed proteomes in rodent models and can be used to advance our current understanding of vascular endothelial dysfunction pathogenesis and progression in a wide range of disease settings.

Aims: Royal jelly (RJ) has a variety of reported biological activities, including vasorelaxation and blood pressure-lowering effects. Although functional foods are positively used for health, the effects of RJ on the cardiovascular system in healthy individuals have not been well studied. Therefore, we investigated the mechanisms underlying the vasorelaxation effects of RJ in healthy control rats to evaluate whether the peripheral circulation was increased., Main Methods: We used fresh RJ to examine the vasorelaxation effects and related mechanisms in Wistar rats using organ bath techniques. Furthermore, we measured changes in tail blood circulation, systolic blood pressure (sBP), and heart rate (HR) after the oral administration of RJ to control rats and nitro-l-arginine methyl ester (l-NAME)-treated rats (0.5 mg/ml dissolved in distilled drinking water for 1 week). Concentrations of acetylcholine (ACh) in the RJ were measured using a commercial kit., Key Findings: RJ caused vasorelaxation of isolated rat aortas and superior mesenteric arteries, and this effect was inhibited by atropine (10 -5 M, 15 min) or L-NAME (10 -4 M, 20 min) and endothelium-denuded arterial ring preparations. Oral RJ increased tail blood flow and mass in control rats 1 h after treatment without affecting velocity, sBP, or HR. These effects were not observed in L-NAME-treated rats. RJ contained approximately 1000 μg/g of ACh., Significance: The present study demonstrated that RJ is composed of muscarinic receptor agonist(s), likely ACh, and induces vasorelaxation through nitric oxide (NO) production from the vascular endothelium of healthy rats, leading to increased tail blood circulation. Thus, fresh RJ may improve peripheral circulation in healthy individuals., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease ( CKD ). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD , not only by direct effects on the endothelium but also by an increment of α-Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia-induced endothelial damage and the extent to which this was dependent on increased α-Klotho concentrations. Methods and Results In a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial-gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α-Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real-time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro-permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial-cadherin-based cell-cell junctions and diminished F-actin stress fiber organization, preventing the formation of endothelial intracellular gaps. Conclusions Our results demonstrate that paricalcitol attenuates the CKD -induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell-cell interactions.

The purpose of this study was to determine the effects of resveratrol and regular aerobic exercise on vascular functions and biomarkers related to vessel responsiveness in an age and gender-dependent manner. The study used young (3 months) and old (12 months) male and female Wistar albino rats. Resveratrol was given in the drinking water (0.05 mg/ml; approximately 7.5 mg/kg) for 6 weeks. In the exercise group, all rats performed treadmill running at 20 m/min on a 0° incline, 40 min/day, 3 times a week, for 6 weeks. Acetylcholine-induced, endothelium-dependent and sodium nitroprusside-mediated, endothelium-independent relaxations of rat thoracic aorta and blood levels of biomarkers were separately changed by resveratrol intake and exercise-training in an age and gender-dependent manner. Antioxidant enzymes and eNOS expressions in vessels were elevated by resveratrol and exercise. Resveratrol and exercise enhanced gene expressions of non-selective PDE1, 2, 3 and cAMP selective PDE4 but not cGMP selective PDE5 in the aorta. In addition, the aortic mRNA expression of inflammation markers were altered by resveratrol and exercise-training. The results of the study demonstrated that vessel responsiveness and biomarkers related to vascular functions were altered by resveratrol consumption and exercise-training in an age and gender-dependent manner., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Renin-angiotensin axis plays a pivotal role in the cardiovascular system, and Angiotensin II (Ang II) is of great importance in the progression of hypertension. Vasoactive peptide intermedin (IMD) belongs to calcitonin gene-related peptide (CGRP) family, which is involved in the regulation of the cardiovascular function. This study aims to determine the effect of vasoactive peptide intermedin on vascular collagen remodeling caused by angiotensin II-induced hypertension., Materials and Methods: 12-week old rats were randomly assigned into three groups, and each group consisted of 12 rats. Rats were administered with Ang II or Ang II+IMD, respectively. Control group received saline administration. Blood pressure of caudal artery was examined two weeks after administration. Serum procollagen I and III were detected by enzyme-linked immunosorbent assay (ELISA). The vascular microstructure was examined via hematoxylin-eosin (HE) staining to evaluate vascular collagen remodeling. Expressions of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) were tested by using Western-blot and RT-PCR., Results: Compared with the control group (92.2±9.1 mmHg), blood pressure of group Ang II was increased by 88% (173.1±11.2 mmHg) (p<0.01). Moreover, blood pressure level in group Ang II+IMD (131.0±10.9 mmHg) was reduced compared to that in group Ang II (p<0.05). Compared with that in control group, higher level of serum procollagen, with significantly increasing vascular W/C ratio and collagen area percentage, was found in group Ang II, while all testing indexes above in group Ang II+IMD were lower than that in group Ang II. No differences were detected in the levels of Akt and MAPK mRNA among all three groups. However, highest expressions of phosphorylation Akt and MAPK protein were shown in group Ang II, and the levels were gradually lower in groups of Ang II+IMD and control., Conclusions: IMD could attenuate the vascular collagen remodeling caused by angiotensin II-induced hypertension via inhibiting phosphorylation of Akt and MAPK.

Importance: Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD., Objective: To examine the effect of ciprofloxacin on AAD development in mice., Design, Setting, and Participants: In a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells., Results: No notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P < .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin-a DNA topoisomerase inhibitor-caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression., Conclusions and Relevance: Ciprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.

The study aimed to evaluate if maternal exposure to fluoxetine (FLX) during pregnancy and lactation would result in altered aortic reactivity in adult offspring. We also sought to understand the role of endothelium derived relaxing factors in aortic response. Wistar rats (75–80 days old), whose progenitors had received FLX (5 mg/kg, FLX offspring) or tap water (control offspring) during pregnancy and lactation were anesthetized, after which the aorta was removed and cut into two rings, one with (Endo+) and the other without (Endo-) endothelium. Concentration-effect curves for acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (Phe) were performed. The vasodilation to ACh and SNP was similar between control and FLX groups in both male and female offspring. In male rats, the response to Phe was similar between the FLX and control groups on Endo+ and Endo- rings. The response to Phe was reduced on Endo+ rings from female FLX when compared with the control group. The endothelium removal, as well as L-NAME, indomethacin, and tranylcypromine incubation corrected the reduced Phe-induced contraction in the aorta from the female FLX group. On the other hand, catalase, NS-398, and L-NIL did not interfere with the vasoconstriction. The aortic level of nitric oxide (NO) was higher in the female FLX than the control group. Although endothelial NO synthase isoform and cyclooxygenase (COX)-1 expressions were similar between the groups, there was a notable increment in neuronal NO synthase expression in the aorta of FLX-exposed female rats, suggesting an important role of this enzyme in the higher levels of NO. Our results show that developmental exposure to FLX causes sex-specific alteration in aortic function through a mechanism involving endothelial factors, probably NO and COX-1 products.

Introduction and Objectives: The aim of this study was to evaluate the effect of aliskiren on aortic stiffness in patients with Marfan syndrome (MS)., Methods: Twenty-eight MS patients (mean age ± standard deviation: 32.6 ± 10.6 years) were recruited from November 2009 to October 2014. All patients were receiving atenolol as standard beta-blocker therapy. A prospective randomization process was performed to assign participants to either aliskiren treatment (150-300mg orally per day) or no aliskiren treatment (negative control) in an open-label design. Central aortic distensibility and central pulsed wave velocity (PWV) by magnetic resonance imaging (MRI), peripheral PWV, central aortic blood pressure and augmentation index by peripheral tonometry, and aortic dilatation by echocardiography were examined initially and after 24 weeks. The primary endpoint was central aortic distensibility by MRI., Results: In analyses of differences between baseline and 24 weeks for the aliskiren treatment group vs the negative control group, central distensibility (overall; P = .26) and central PWV (0.2 ± 0.9 vs 0.03 ± 0.7 [m/s]; P = .79) by MRI were not significantly different. Central systolic aortic blood pressure tended to be lower by 14mmHg in patients in the aliskiren treatment group than in the control group (P = .09). A significant decrease in peripheral PWV (brachial-ankle PWV) in the aliskiren treatment group (-1.6 m/s) compared with the control group (+0.28 m/s) was noted (P = .005)., Conclusions: Among patients with MS, the addition of aliskiren to beta-blocker treatment did not significantly improve central aortic stiffness during a 24-week period., (Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Annonacin (1) was isolated from the North American pawpaw ( Asimina triloba), as reported earlier from these laboratories. Natural 1 was submitted to the rat aortic ring bioassay for evaluation of antiangiogenic activity and was found to inhibit microvessel growth (IC 50 value of 3 μM). 4,10,15,20-Tetraazido derivatives of 1 were prepared by permesylation followed by azide displacement or by iodination followed by azide displacement. The tetraazide derived from mesylation/azidation was antiangiogenic, while that derived from iodination/azidation exhibited no appreciable activity. The membrane permeability of natural 1 was evaluated using the parallel artificial membrane permeability assay and was found to be marginally permeable as compared to several clinically relevant compounds.

The purposes of this study were to evaluate the expression of retinol-binding protein 4 (RBP4) in diabetic rats with atherosclerosis and to investigate the role of vitamin D intervention. Male Wistar rats were randomly divided into 4 groups, including the control group (NC), the diabetic rats (DM1), the untreated diabetic atherosclerosis rats (DM2), and the vitamin D-treated diabetic atherosclerosis rats (DM3). The levels of serum and adipose RBP4, fasting insulin (FINS), fasting plasma glucose (FPG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), 25-hydroxyvitamin D [25(OH)D], C-reactive protein (CRP), and systolic blood pressure (SBP) were measured. Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment β -cell function index (HOMA- β ), and atherogenic indexes (AI) were calculated. Compared with group NC, the levels of RBP4, TG, LDL-c, FPG, FINS, CRP, AI1, AI2, SBP, and HOMA-IR increased, while the levels of HDL-c, 25(OH)D, and HOMA- β decreased in groups DM1 and DM2. After 8 weeks of vitamin D supplementation in group DM3, the levels of 25(OH)D and HOMA- β increased and the levels of LDL-c, TC, HOMA-IR, FINS, CRP, RBP4, AI1, AI2, and SBP decreased significantly when compared with group DM2 ( P < 0.05); Pearson analysis showed that serum RBP4 was positively correlated with TG, FINS, HOMA-IR, SBP, CRP, and AI and negatively correlated with 25(OH)D. In addition, multivariable logistic regression analysis showed that serum RBP4, SBP, and HDL-c were predictors for the presence of diabetic atherosclerosis. These findings suggested that RBP4 could involve in the improvement of diabetic atherosclerosis; vitamin D had the ability to decrease the level of RBP4 and eventually played an important role in preventing atherosclerosis in diabetes.

Coronary heart disease is a vital cause of morbidity and mortality worldwide, and calcium channel blockers (CCBs) are important drugs that can be used to treat cardiovascular diseases. Suxiao Jiuxin Pill (SX), a traditional Chinese medicine, is widely used as an emergency drug for coronary heart disease therapy. However, understanding its potential mechanism in intracellular calcium concentration ([Ca 2+ ] i ) modulation remains a challenge. To identify the active pharmacological ingredients (APIs) and reveal a novel combination therapy for ameliorating cardiovascular diseases, the ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) combined with a dual-luciferase reporter [Ca 2+ ] i assay system was applied. Ligustrazine, ferulic acid, senkyunolide I, senkyunolide A and ligustilide were identified as potential calcium antagonists in SX, and the combination of ligustrazine and senkyunolide A showed synergetic calcium antagonistic activity. Additionally, the synergetic mechanism was further investigated by live-imaging analysis with the Ca 2+ indicator fluo-4/AM by monitoring fluorescence changes. Our results indicated that ligustrazine can block voltage-operated Ca 2+ channels (VDCCs) effectively and senkyunolide A can exert an inhibition effect mostly on ryanodine receptors (RYRs) and partly on VDCCs. Finally, an arterial ring assay showed that the combination of ligustrazine and senkyunolide A exerted a better vasodilatation function than using any components alone. In this study, we first revealed that a pair of natural APIs in combination acting on VDCCs and RYRs was more effective on vasodilatation by regulating [Ca 2+ ] i ., (Copyright © 2018. Published by Elsevier B.V.)

Several studies have already confirmed the specific vasomotor effect of hydrogen sulfide (H 2 S) and its interaction with the nitric oxide (NO) system in normotensive rats, but results in spontaneously hypertensive rats (SHRs) are limited. the aim of this study was to describe the age- and blood pressure-dependent effects of endogenous NO and exogenous Na 2 S and their interaction in vasomotor responses of the thoracic aorta (TA) in normotensive Wistar rats and SHRs. the systolic blood pressure (sBP), vasoactivity, NO-synthase (NOS) expression and activity, cystathionine gamma-lyase (CSE) expression, and geometry of the isolated TA were evaluated at 4 and 16 weeks of age. Although hypertrophy of the heart was observed in young and adult SHRs, the sBP was increased only in adulthood. the contractile responses were decreased in young as in adult SHRs with the key participation of the endogenous NO system. however, the hypotrophy in the young and the hypertrophy (mainly at the expense of extracellular matrix) in the adult SHRs were found in the TA. While unchanged in young SHRs, in adult SHRs, partially impaired endothelial function was confirmed. Nevertheless, the NO-dependent component of acetylcholine-induced relaxation was higher in both young and adult SHRs. Consistently, even though there was an age-dependent decrease in NOS activity in both strains, NOS activity was higher in both young and adult SHRs compared to age-matched normotensive rats. Application of exogenous Na 2 S evoked a concentration-dependent dual vasoactive effect of TAs in both strains, regardless of age. Increased sensitivity in favor of vasorelaxant responses of Na 2 S in prehypertensive SHRs, and an enhanced maximal vasorelaxation in adult SHR was observed. the acute NO inhibition generally increased the relaxant phase of Na 2 S responses; nevertheless, the development of hypertension potentiated this effect. the TA of the SHRs is endowed with a unique inherent predisposition of vasoactive mechanisms, which serve as compensatory processes during the developed stage of hypertension: the NO component and H 2 S signaling pathways are implicated. the decreased contractility seems to be a deleterious effect. the increased participation of the H 2 S system on vasorelaxation after acute NO inhibition could be considered a reserved mechanism in case of endogenous NO deficiency.

Background: Testosterone, 5α- and 5β-dihydrotestosterone (-DHT) induce an acute in vitro vasorelaxation and in vivo vasodepressor, hypotensive and antihypertensive responses. Our aim was to study whether androgen-induced blood pressure (BP) reduction is involved with a blockade of Ca 2+ influx through L-type voltage-operated calcium channels (L-VOCCs) and/or the signaling pathways of α 1 -adrenoceptors to induce vasoconstriction, which are one of the major mechanisms of BP maintenance., Materials and Methods: The relaxing potency and efficacy of each androgen in large conduit (thoracic aorta) and resistance (mesenteric) arteries from male hypertensive (SHR) and normotensive (WKY) rats were established. Blood vessels were isometrically recorded and precontracted with KCl or phenylephrine (Phe)., Results: Androgens induced concentration-dependent vasorelaxation in precontracted arteries from SHR and WKY rats. 5β-DHT was always the most potent vasorelaxant in arteries from SHR. The KCl-induced contraction resulted significantly more sensitive to androgen-induced vasorelaxation than the Phe-induced contraction. On Phe-induced contraction, 5β-DHT was more potent in the mesenteric artery than in the thoracic aorta., Conclusions: The vasorelaxation induced by androgens is mainly mediated by blocking L-VOCCs and in lesser extent by the blockade of multiple signaling pathways operative during α-adrenoceptor-induced vasoconstriction. 5β-DHT regulates vascular resistance and BP by mainly acting in the mesenteric arterial bed, which may explain its outstanding antihypertensive response previously reported.

Objectives High glucose-induced alterations in vascular smooth muscle cell behavior have not been fully characterized. We explored the protective mechanism of tetramethylpyrazine (TMP) on rat smooth muscle cell injury induced by high glucose via the mitogen-activated protein kinase (MAPK) signaling pathway. Methods Vascular smooth muscle cells (VSMCs) isolated from rat thoracic aortas were divided into control, high glucose (HG), and pre-hatching TMP groups. The effect of different glucose concentrations on cell viability and on the migration activity of VSMC cells was examined using MTT analysis and the wound scratch assay, respectively. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using enzyme-linked immunoassays. The levels of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38MAPK, and MAPK phosphorylation were assessed by western blotting. Results Cell proliferation was remarkably increased by increased glucose concentrations. Compared with the HG group, the migratory ability of VSMC cells was reduced in the presence of TMP. TMP also decreased the MDA content in the supernatant, but significantly increased the SOD activity. Western blotting showed that TMP inhibited the phosphorylation of JNK, p38MAPK, and ERK. Conclusions TMP appears to protect against HG-induced VSMC injury through inhibiting reactive oxygen species overproduction, and p38MAPK/JNK/ERK phosphorylation.

Heat shock proteins (HSPs) play an important role in the cellular adaptation to stress, a requisite for cell survival. The aortic wall appears to be a target for increased expression of HSPs during surgical stress. We aimed to define the expression and function of aortic HSP70 in 31 patients with normal ascending thoracic aortic diameter who underwent aortic valve replacement due to aortic valve stenosis and in 35 patients with dilated ascending thoracic aorta who underwent replacement of an ascending thoracic aortic aneurysm. To elucidate responsible signaling mechanisms we used an in vitro model of rat hypoxic aortic vascular smooth muscle cell (AVSMC) cultures. We demonstrated an increase in AVSMC HSP70 and an attenuation of the apoptotic markers (TUNEL-positive nuclei, caspase-3 activity, Bax/Bcl2 ratio) in aortic wall tissue specimens from both aortic valve stenosis and ascending thoracic aortic aneurysm patients on β1 blockade with metoprolol. In vitro, metoprolol treatment of hypoxic rat AVSMCs increased nitric oxide (NO) production, induced heat shock factor 1 transport to the nucleus, upregulated HSP70, decreased p53 phosphorylation and attenuated apoptosis. Blockade of NO production, resulted in decreased HSP70 and prevented the metoprolol-induced anti-apoptotic response of hypoxic AVSMCs. We demonstrate an anti-apoptotic effect of metoprolol dependent on NO-induced HSP70 expression, and thus augmentation of HSP70 expression should be considered as a therapeutic approach to limit apoptosis in the human ascending thoracic aorta of patients undergoing cardiac surgery.

Objectives: Ischaemia reperfusion (IR) injury occurs during vascular graft harvesting and implantation during vascular/cardiac surgery. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective endothelial protection in different pathophysiological conditions. The hypothesis that the phosphodiesterase-5 inhibitor vardenafil would protect vascular grafts against IR injury by upregulating the nitric oxide-cGMP pathway in the vessel wall of the bypass graft was investigated., Methods: Lewis rats (n = 6-7/group) were divided into Group 1, control; Group 2, donor rats received intravenous saline; Group 3, received intravenous vardenafil (30 μg/kg) 2 h before explantation. Whereas aortic arches of Group 1 were immediately mounted in an organ bath, aortic segments of Groups 2 and 3 were stored for 2 h in saline and transplanted into the abdominal aorta of the recipient. Two hours after transplantation, the implanted grafts were harvested. Endothelium dependent and independent vasorelaxations were investigated. TUNEL, CD-31, ICAM-1, VCAM-1, α-SMA, nitrotyrosine, dihydroethidium and cGMP immunochemistry were also performed., Results: Compared with the control, the saline group showed significantly attenuated endothelium dependent maximal relaxation (R max ) 2 h after reperfusion, which was significantly improved by vardenafil supplementation (R max control, 91 ± 2%; saline 22 ± 2% vs. vardenafil 39 ± 4%, p < .001). Vardenafil pre-treatment significantly reduced DNA fragmentation (control 9 ± 1%, saline 66 ± 8% vs. vardenafil 13 ± 1%, p < .001), nitro-oxidative stress (control 0.8 ± 0.3, saline 7.6 ± 1.3 vs. vardenafil 3.8 ± 1, p = .036), reactive oxygen species level (vardenafil 36 ± 4, control 34 ± 2 vs. saline 43 ± 2, p = .049), prevented vascular smooth muscle cell damage (control 8.5 ± 0.7, saline 4.3 ± 0.6 vs. vardenafil 6.7 ± 0.6, p = .013), decreased ICAM-1 (control 4.1 ± 0.5, saline 7.0 ± 0.9 vs. vardenafil 4.4 ± 0.6, p = .031), and VCAM-1 score (control 4.4 ± 0.4, saline 7.3 ± 1.0 vs. vardenafil 5.2 ± 0.4, p = .046) and increased cGMP score in the aortic wall (control 11.2 ± 0.8, saline 6.5 ± 0.8 vs. vardenafil 8.9 ± 0.6, p = .016). The marker for endothelial integrity (CD-31) was also higher in the vardenafil group (control 74 ± 4%, saline 22 ± 2% vs. vardenafil 40 ± 3%, p = .008)., Conclusions: The results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction of an arterial graft after bypass surgery, which can effectively be prevented by vardenafil. Its clinical use as preconditioning drug could be a novel approach in vascular/cardiac surgery., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

We studied the effects of treatment with SMe1EC, a hexahydropyridoindole antioxidant, on vascular reactivity, endothelial function, and oxidonitrosative stress level of thoracic aorta in young and old rats with or without diabetes mellitus. The rats were grouped as young control (YC 3 months old), old control (OC 15 months old), young diabetic (YD), old diabetic (OD), young control treated (YCT), old control treated (OCT), young diabetic treated (YDT), and old diabetic treated (ODT). Diabetes was induced by streptozotocin injection and subsequently SMe1EC2 (10 mg/kg/day, p.o.) was administered to YCT, OCT, YDT, and ODT rats for 5 months. In young and old rats, diabetes resulted in hypertension, weight loss, hyperglycemia, and hypertriglyceridemia, which were partially prevented by SMe1EC2. SMe1EC2 also inhibited the diabetes-induced increase in aorta levels of AGEs (advanced glycosylation end-protein adducts), 4-HNE (4-hydroxy-nonenal-histidine), 3-NT (3-nitrotyrosine), and RAGEs (receptors for AGEs). The contractions of the aorta rings to phenylephrine (Phe) and KCL did not significantly change, but acetylcholine (ACh) and salbutamol relaxations were reduced in OC compared to YC rats. Diabetes induction increased Phe contractions in YC and OC rats, KCL contractions in YC rats, and did not cause further inhibition in already inhibited ACh and salbutamol relaxations in OC rats. We have achieved the lowest levels of ACh relaxation in YD rats compared to other groups. SMe1EC2 did not change the response of aorta to ACh, salbutamol and Phe in YC rats, and ameliorated ACh relaxations in OC and YD but not in OD rats. In YDT and ODT rats, increased Phe and KCL contractions, high blood pressure, and impaired salbutamol relaxations were amended by SMe1EC2. Phe contractions observed in YD and OD rats as well as KCl contractions observed in OC rats were the lowest levels when the rats were treated with SMe1EC2. When the bath solution was shifted to cyclopiazonic acid (CYP) or CYP plus Ca 2+ -free medium, the contraction induced by a single dose of Phe (3 × 10 -6  M) was more inhibited in YD and OD than in YC but not in OC rats. In SMe1EC2-treated rats, neither the presence of CFM nor CFM plus CYP exhibited a significant change in response of aorta to a single dose of Phe. These findings suggest that α1-adrenergic receptor signaling is activated in both age groups of diabetic rats, diabetes activates K + -depolarization and calcium mobilization via Ca V especially in the aorta of young rats, and sensitizes the aorta of old rats to the regulating effect of SMe1EC2. ACh relaxations were inhibited in YC rats, increased in OC rats and unchanged in YD and OD rats when aortic rings pretreated with TEA, an inhibitor of calcium-activated K + channels (K Ca ), or 4-aminopyridine (4-AP), an inhibitor of voltage-sensitive K + channels (K V ). ACh relaxations were inhibited in YCT, OCT, and YDT rats in the presence of 4-AP or TEA. In ODT rats, 4-AP did not change ACh relaxation but TEA inhibited. These findings suggest that the contribution of K v and K Ca to ACh relaxation is likely upregulated by SMe1EC2 when the relaxations were inhibited by aging or diabetes. We conclude that SMe1EC2 might be a promising agent for aging and diabetes related vascular disorders.

Background and Aims: Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe -/- ) mice., Methods: Eight-week-old male apoe -/- mice were fed a western-type diet (WTD) supplemented with 0.1% ticagrelor (approximately 120 mg/kg/day). Non-treated animals on WTD served as control. Atherosclerotic lesions were examined by en-face Sudan IV staining, histological analyses, quantitative RT-PCR analysis, and western blotting. Endothelial function was analyzed by acetylcholine-dependent vasodilation using aortic rings. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments., Results: Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05)., Conclusions: Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Compounds containing a nitro group may reveal vasodilator properties. Several nitro compounds have a NO 2 group in a short aliphatic chain connected to an aromatic group. In this study, we evaluated in rat aorta the effects of two nitro compounds, with emphasis on a putative recruitment of the soluble guanylate cyclase (sGC) pathway to induce vasodilation. Isolated aortic rings were obtained from male Wistar rats to compare the effects induced by 2-nitro-1-phenylethanone (NPeth) or 2-nitro-2-phenyl-propane-1,3-diol (NPprop). In aortic preparations contracted with phenylephrine or KCl, NPeth and NPprop induced vasorelaxant effects that did not depend on the integrity of vascular endothelium. NPeth had a lesser vasorelaxant efficacy than NPprop and only the NPprop effects were inhibited by pretreatment with the sGC inhibitors, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or methylene blue. In an ODQ-preventable manner, NPprop inhibited the contractile component of the phenylephrine-induced response mediated by intracellular Ca 2+ release or by extracellular Ca 2+ recruitment through receptor- or voltage-operated Ca 2+ channels. In contrast, NPprop was inert against the transient contraction induced by caffeine in Ca 2+ -free medium. In an ODQ-dependent manner, NPprop inhibited the contraction induced by the protein kinase C activator phorbol 12,13-dibutyrate or by the tyrosine phosphatase inhibitor sodium orthovanadate. In silico docking analysis of a sGC homologous protein revealed preferential site for NPprop. In conclusion, the nitro compounds NPeth and NPprop induced vasorelaxation in rat aortic rings. Aliphatic chain substituents selectively interfered in the ability of these compounds to induce vasorelaxant effects, and only NPprop relaxed aortic rings via a sGC pathway., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Chronic ethanol consumption is associated with hypertension and atherosclerosis. Vascular oxidative stress is described as an important mechanism whereby ethanol predisposes to atherosclerosis. We hypothesized that nebivolol would prevent ethanol-induced hypertension and vascular oxidative stress., Methods: Male Wistar rats were treated with ethanol 20% (vol./vol.) or nebivolol (10 mg/kg/day, p. o., gavage), a selective β 1 -adrenergic receptor antagonist., Results: Ethanol-induced increase in blood pressure and in the circulating levels of adrenaline and noradrenaline was prevented by nebivolol. Similarly, nebivolol prevented ethanol-induced increase in plasma levels of renin, angiotensin I and II. Chronic ethanol consumption increased the aortic levels of superoxide anion (O 2 - ), thiobarbituric acid reactive species (TBARS) as well as the expression of Nox1 and nitrotyrosine immunostaining in the rat aorta. Treatment with nebivolol prevented these responses. The decrease in aortic levels of nitrate/nitrite (NOx) induced by ethanol was prevented by the treatment with nebivolol. Finally, nebivolol attenuated ethanol-induced increase in phenylephrine- and noradrenaline-induced contraction of endothelium-intact and endothelium-denuded aortic rings., Conclusions: The novelty of our study is that nebivolol prevented ethanol-induced hypertension and vascular oxidative stress. Additionally, we showed that the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) are important endogenous mediators of the cardiovascular effects of ethanol., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chondroitin sulphate (CS) has long been used to treat osteoarthritis. Some investigations have also shown that the treatment with CS could reduce coronary events in patients with heart disease but no studies have identified the mechanistic role of these therapeutic effects. We aimed to investigate how the treatment with CS can interfere with the progress of atherosclerosis. The aortic arch, thoracic aorta and serum were obtained from apolipoprotein E (ApoE) knockout mice fed for 10 weeks with high-fat diet and then treated with CS (300 mg/kg, n  = 15) or vehicle ( n  = 15) for 4 weeks. Atheromatous plaques were highlighted in aortas with Oil Red staining and analysed by microscopy. ApoE knockout mice treated with CS exhibited attenuated atheroma lesion size by 68% as compared with animals receiving vehicle. Serum lipids, glucose and C-reactive protein were not affected by treatment with CS. To investigate whether CS locally affects the inflamed endothelium or the formation of foam cells in plaques, human endothelial cells and monocytes were stimulated with tumour necrosis factor α or phorbol myristate acetate in the presence or absence of CS. CS reduced the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and ephrin-B2 and improved the migration of inflamed endothelial cells. CS inhibited foam cell formation in vivo and concomitantly CD36 and CD146 expression and oxidized low-density lipoprotein uptake and accumulation in cultured activated human monocytes and macrophages. Reported cardioprotective effects of CS may arise from modulation of pro-inflammatory activation of endothelium and monocytes and foam cell formation., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)