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Epidemiological evidence showed that chronic ethanol consumption is a major risk factor in the development of impotence. The present study investigated the effects of carbachol-, electrical field stimulation (EFS)-, sodium nitroprusside (SNP)- and papaverine-induced relaxant responses in the isolated corpus cavernosum tissues from rabbits submitted to an 12-week course of chronic low (5% v/v) or high ethanol intake (30% v/v). Increased carbachol- and EFS-induced relaxant responses but not SNP and papaverine, were observed in low ethanol-fed rabbits compared with controls. However, impaired carbachol- and EFS-induced relaxant responses were observed in high ethanol-fed rabbits compared with control rabbits. There were no significant differences in SNP- and papaverine-induced relaxant responses between control and high ethanol-fed rabbits. In addition, decreased neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS) immunoreactivity in penile tissue were found in high ethanol-fed rabbits, but increased the immunoreactivity in low ethanol-fed group, compared with control group. These results suggest that alterations in nitric oxide (NO) production within the cavernous tissue in the high ethanol-fed rabbits are, at least in part, responsible for the erectile dysfunction.

Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12–14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer’s disease (AD). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. KD also increased the relative abundance of putatively beneficial gut microbiota ( Akkermansia muciniphila and Lactobacillus ), and reduced that of putatively pro-inflammatory taxa ( Desulfovibrio and Turicibacter ). We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD.

Background: The present study was conducted to investigate the role of renal ischemia-reperfusion (IR) and angiotensin II (ANG II) on mRNA and protein levels of renal dihydrofolate reductase (DHFR), GTP-cyclohydrolase 1 (GTP- CH 1), and endothelial and inducible nitric oxide synthase (eNOS and iNOS, respectively). Methods: Male Wistar rats were sham operated or received IR (30 min occlusion, and reperfusion for 1 day). Each group was treated separately with water, angiotensin-converting enzyme inhibitor (ACEI) and ANG II receptor type 1 blocker (ARB) for 1 day before the sham operation or IR, and continuously for 1 day after the operation. The mRNA and protein levels were detected by RT-PCR and Western blot, respectively. Results: IR decreased DHFR mRNA and protein levels (p < 0.01), both of which were restored by ACEI or ARB, whereas GTP-CH 1 expression was unaltered. IR suppressed eNOS dimer while enhancing the monomer (p < 0.01). IR augmented iNOS mRNA, total iNOS protein and iNOS monomer (all p < 0.01) which were attenuated by ACEI or ARB. Conclusion: Our study is the first to demonstrate that the heightened ANG II in IR, via stimulation of ANG II receptor type 1, suppresses DHFR and eNOS dimer, while activating both iNOS mRNA and protein levels.

Endometriosis is a common disease characterised by ectopic growth of endometrial tissue outside the uterine cavity. Angiogenesis has been implicated in the pathogenesis of the disease; some molecules, like hypoxia-inducible factor-1alpha (HIF-1alpha) and neuronal, endothelial and inducible nitric oxide synthase isoforms (nNOS, eNOS and iNOS), are known as proangiogenetic factors. We evaluated expression of these molecules by immunohistochemistry in 32 cases of ovarian endometriomas, formalin-fixed and paraffin-embedded. Analysis was focused on the cells composing the inner layer of the cyst, constituted by the ectopic endometrial glands, stromal cells and vessels, and the outer one, constituted by a fibrous layer of fibroblasts and vessels. We found that epithelial glands and capsular vessel endothelial cells showed a correlated expression of NOS isoforms; that expression of nNOS, iNOS and HIF-1alpha was correlated in epithelial glands and capsular fibroblasts; that vessel endothelial cells showed a higher mean expression for all the proangiogenetic molecules in the outer layer than in the inner one; and that capsular fibroblasts showed a higher mean expression for HIF-1alpha, iNOS and eNOS compared to the specialised stromal cells of the inner layer. Our data seem to indicate that angiogenesis is stimulated more in the outer capsule than in the inner layer of ovarian endometriotic cysts. The knowledge of the complex mechanisms associated to angiogenesis might be useful in a therapeutic approach of ovarian endometriosis based on anti-angiogenetic drugs. The therapeutic target would be mainly the capsular vasculature, more than the vasculature of ectopic endometrial tissues.

Background: Hypotension is a common adverse effect associated with the use of propofol and sodium thiopental. The objective of this study was to examine the impact of thiopental and propofol on erythrocyte (RBC) nitric oxide (NO) synthase activity and RBC-mediated NO release. Methods: A prospective, interventional in vitro trial. Male patients aged between 18 and 45 years with a classification of American Society of Anesthesiologists (ASA) class I, defined as healthy individuals, were included in this study. Venous blood samples (20 mL) were obtained from patients who met the inclusion criteria. Measurements were performed using the specific fluorescent probes for NO and calcium (Ca2+). Propofol and sodium thiopental were added to the suspensions at doses of 100, 250, 500, and 1000 μM and incubated for 30 min. All suspensions were proceeded to flow cytometric analysis. Nitrite/nitrate concentration was measured in the supernatant of RBC suspensions after centrifugation. RBC deformability and aggregation were measured by laser diffraction analysis using an ektacytometer. The primary outcome was to evaluate the effects of sodium thiopental and propofol on RBC-NOS activity. Results: Sodium thiopental caused significant increase in intracellular NO concentrations at all doses studied (p < 0.001). Importantly, the intracellular NO concentration increment was positively correlated with sodium thiopental concentration in the suspensions. The presence of L-N-acetylmethyl-arginine in the experimental medium abolished NO production in RBCs in response to sodium thiopental. Sodium thiopental caused increased nitrite and nitrate levels in the suspension medium in a dose-dependent manner. Incubation with thiopental caused an increase in intracellular free Ca+2 levels while propofol induced no change. Sodium thiopental and propofol caused significant decrement in RBC aggregation. Conclusions: This study presents the initial evidence of augmented RBC-mediated NO production and release in response to sodium thiopental administration. In contrast to the effects observed with sodium thiopental, our results demonstrated that propofol had no impact on RBC-mediated NO production.

Background & objectives: Striatin is a multi-domain scaffolding protein essential for activating endothelial nitric oxide synthase (eNOS). However, its role in pre-eclampsia remains use explored. Hence, this study aimed to investigate the association between striatin and eNOS in regulating nitric oxide (NO) production in the placenta of women with and without pre-eclampsia. Methods: Forty pregnant women each without (controls) and with pre-eclampsia (cases) were enrolled in the study. Blood striatin and NO concentrations were detected by the ELISA. Protein expression of striatin, phosphorylated eNOS (peNOS), inducible NOS (iNOS) and phosphorylated NF-κB were measured in the placental tissues by Western blot. Twenty four hour urinary protein and serum urea, uric acid and creatinine were analyzed as an autoanalyzer. Placental histology was analyzed by haematoxylin and eosin staining. Results: Compared to normotensive pregnant women, the levels of serum NO and striatin were decreased in pre-eclamptic women. The protein expression of striatin and peNOS was significantly reduced (P<0.05) while p65NF-κB and iNOS were upregulated considerably (P<0.05) in the placenta of cases compared to controls. Interpretation & conclusions: Our results show for the first time that decreased striatin expression was associated with decreased peNOS protein expression in the placental tissue of pre-eclamptic women. Interestingly, no significant difference was found in blood striatin or NO levels between controls and cases. Thus, therapies that improve placental striatin expression are attractive possibilities, both for prevention as well as treatment of endothelial dysfunction in pre-eclampsia.

Rationale Nitric oxide is an important regulator of vascular tone in the pulmonary circulation. Surgical correction of congenital heart disease limits pulmonary hypertension to a brief period. Objectives The study has measured expression of endothelial (eNOS), inducible (iNOS), and neuronal nitric oxide synthase (nNOS) in the lungs from biopsies of infants with pulmonary hypertension secondary to cardiac abnormalities (n = 26), compared to a control group who did not have pulmonary or cardiac disease (n = 8). Methods eNOS, iNOS and nNOS were identified by immunohistochemistry and quantified in specific cell types. Measurements and main results Significant increases of eNOS and iNOS staining were found in pulmonary vascular endothelial cells of patients with congenital heart disease compared to control infants. These changes were confined to endothelial cells and not present in other cell types. Patients who strongly expressed eNOS also had strong expression of iNOS. Conclusion Upregulation of eNOS and iNOS occurs at an early stage of pulmonary hypertension, and may be a compensatory mechanism limiting the rise in pulmonary artery pressure.

The role of oxidative stress in different aortopathies is evaluated. Thirty-two tissue samples from 18 men and 14 women were divided into: 4 control (C) subjects, 11 patients with systemic arterial hypertension (SAH), 4 with variants of Marfan’s syndrome (MV), 9 with Marfan’s syndrome (M), 2 with Turner’s syndrome, and 2 with Takayasu’s arteritis (TA). Aorta fragments were homogenized. Lipoperoxidation (LPO), copper-zinc and manganese superoxide dismutase (Mn and Cu-Zn-SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), endothelial nitric oxide synthase (eNOS), nitrates and nitrites ( NO 3 − / NO 2 − ), and type IV collagen, and laminin were evaluated. There was an increase in Mn- and Cu-Zn-SOD activity in SAH, MV, M, and Turner’s syndrome. There was also an increase in CAT activity in M and Turner’ syndrome. GPx and GST activity decreased and LPO increased in all groups. eNOS was decreased in SAH, MV, and M and NO 3 − / NO 2 − were increased in SAH and TA. Type IV collagen was decreased in Turner’s syndrome and TA. Laminin γ -1 was decreased in MV and increased in M. In conclusion, similarities and differences in oxidative stress in the different aortopathies studied including pathologies with aneurysms were found with alterations in SOD, CAT, GPx, GST, and eNOS activity that modify subendothelial basement membrane proteins.

Nitric oxide (NO) is considered to be involved in the modulation of uterine contractility. In the present pilot study, the direct detection of intracellular NO in pregnant human myometrial tissues has been investigated by using the fluorescent indicator 4,5-diaminofluorescein-2 diacetate (DAF-2DA). Pregnant myometrial tissue samples were obtained during Cesarean sections between week 34 and 40 of gestation before the onset of labor. Living explants were loaded with 10 μM DAF-2DA, stimulated with 1 mM arginine, subsequently fixed with glutaraldehyde and examined by fluorescence microscopy. The presence of NO synthases (NOS) was studied by immunohistochemistry. After application of DAF-2DA, DAF fluorescence was located primarily in blood vessels and to a minor extent in myometrial cells. By immunohistochemistry, strong endothelial NOS (eNOS) staining was found in vessel walls. In myometrial cells weak staining of eNOS and inducible NOS was observed. We conclude that the direct NO detection by DAF-2DA provides a new and independent method to identify sites of NO production in myometrium and other heterogeneous tissues.

Objectives Endothelial cells play an important role in peri-implant angiogenesis during early bone formation. Therefore, interactions between endothelial progenitor cells (EPCs) and titanium dental implant surfaces are of crucial interest. The aim of our in vitro study was to investigate the reactions of EPCs in contact with different commercially available implant surfaces. Materials and methods EPCs from buffy coats were isolated by Ficoll density gradient separation. After cell differentiation, EPC were cultured for a period of 7 days on different titanium surfaces. The test surfaces varied in roughness and hydrophilicity: acid-etched (A), sand-blasted-blasted and acid-etched (SLA), hydrophilic A (modA), and hydrophilic SLA (modSLA). Plastic and fibronectin-coated plastic surfaces served as controls. Cell numbers and morphology were analyzed by confocal laser scanning microscopy. Secretion of vascular endothelial growth factor (VEGF)-A was measured by enzyme-linked immunosorbent assay and expressions of iNOS and eNOS were investigated by real-time polymerase chain reaction. Results Cell numbers were higher in the control groups compared to the cells of titanium surfaces. Initially, hydrophilic titanium surfaces (modA and modSLA) showed lower cell numbers than hydrophobic surfaces (A and SLA). After 7 days smoother surfaces (A and modA) showed increased cell numbers compared to rougher surfaces (SLA and modSLA). Cell morphology of A, modA, and control surfaces was characterized by a multitude of pseudopodia and planar cell soma architecture. SLA and modSLA promoted small and plump cell soma with little quantity of pseudopodia. The lowest VEGF level was measured on A, the highest on modSLA. The highest eNOS and iNOS expressions were found on modA surfaces. Conclusions The results of this study demonstrate that biological behaviors of EPCs can be influenced by different surfaces. The modSLA surface promotes an undifferentiated phenotype of EPCs that has the ability to secrete growth factors in great quantities. Clinical relevance In correlation with recent clinical studies these results underline the hypothesis that EPC could promote and increase neovascularization by secreting paracrine factors which support osseointegration of dental implants.