Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage

The Asp298 allele of endothelial nitric oxide synthase is a risk factor for myocardial infarction among patients with type 2 diabetes mellitus

Background: Endothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM). Given the role of nitric oxide in the vascular system, we aimed to test hypotheses of synergy between the common endothelial nitric oxide synthase (eNOS) Asp(298) allele and T2DM in predisposing to acute myocardial infarction (AMI). Methods: In a population-based patient survey with 403 persons with T2DM and 799 healthy subjects from the population without diabetes or hypertension, we analysed the relation between T2DM, sex and the eNOS Asp(298) allele versus the risk for AMI. Results: In an overall analysis, T2DM was a significant independent risk factor for AMI. In patients with T2DM, homozygosity for the eNOS Asp(298) allele was a significant risk factor (HR 3.12 [1.49-6.56], p = 0.003), but not in subjects without diabetes or hypertension. Compared to wild-type non-diabetic subjects, all patients with T2DM had a significantly increased risk of AMI regardless of genotype. This risk was however markedly higher in patients with T2DM homozygous for the Asp(298) allele (HR 7.20 [3.01-17.20], p < 0.001), independent of sex, BMI, systolic blood pressure, serum triglycerides, HDL -cholesterol, current smoking, and leisure time physical activity. The pattern seemed stronger in women than in men. Conclusion: We show here a strong independent association between eNOS genotype and AMI in patients with T2DM. This suggests a synergistic effect of the eNOS Asp(298) allele and diabetes, and confirms the role of eNOS as an important pathological bottleneck for cardiovascular disease in patients with T2DM

Climate Change and the Potential Spreading of Marine Mucilage and Microbial Pathogens in the Mediterranean Sea

Background: Marine snow (small amorphous aggregates with colloidal properties) is present in all oceans of the world. Surface water warming and the consequent increase of water column stability can favour the coalescence of marine snow into marine mucilage, large marine aggregates representing an ephemeral and extreme habitat. Marine mucilage characterize aquatic systems with altered environmental conditions. Methodology/Principal Findings: We investigated, by means of molecular techniques, viruses and prokaryotes within the mucilage and in surrounding seawater to examine the potential of mucilage to host new microbial diversity and/or spread marine diseases. We found that marine mucilage contained a large and unexpectedly exclusive microbial biodiversity and hosted pathogenic species that were absent in surrounding seawater. We also investigated the relationship between climate change and the frequency of mucilage in the Mediterranean Sea over the last 200 years and found that the number of mucilage outbreaks increased almost exponentially in the last 20 years. The increasing frequency of mucilage outbreaks is closely associated with the temperature anomalies. Conclusions/Significance: We conclude that the spreading of mucilage in the Mediterranean Sea is linked to climate-driven sea surface warming. The mucilage can act as a controlling factor of microbial diversity across wide oceanic regions and could have the potential to act as a carrier of specific microorganisms, thereby increasing the spread of pathogenic bacteria

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis.

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear

Incorporating field wind data to improve crop evapotranspiration parameterization in heterogeneous regions

Accurate parameterization of reference evapotranspiration ( ET0) is necessary for optimizing irrigation scheduling and avoiding costs associated with over-irrigation (water expense, loss of water productivity, energy costs, and pollution) or with under-irrigation (crop stress and suboptimal yields or quality). ET0 is often estimated using the FAO-56 method with meteorological data gathered over a reference surface, usually short grass. However, the density of suitable ET0 stations is often low relative to the microclimatic variability of many arid and semi-arid regions, leading to a potentially inaccurate ET0 for irrigation scheduling. In this study, we investigated multiple ET0 products from six meteorological stations, a satellite ET0 product, and integration (merger) of two stations’ data in Southern California, USA. We evaluated ET0 against lysimetric ET observations from two lysimeter systems (weighing and volumetric) and two crops (wine grapes and Jerusalem artichoke) by calculating crop ET ( ETc) using crop coefficients for the lysimetric crops with the different ET0. ETc calculated with ET0 products that incorporated field-specific wind speed had closer agreement with lysimetric ET, with RMSE reduced by 36 and 45% for grape and Jerusalem artichoke, respectively, with on-field anemometer data compared to wind data from the nearest station. The results indicate the potential importance of on-site meteorological sensors for ET0 parameterization; particularly where microclimates are highly variable and/or irrigation water is expensive or scarce

Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala

Successful Cognitive Aging in Rats: A Role for mGluR5 Glutamate Receptors, Homer 1 Proteins and Downstream Signaling Pathways

Normal aging is associated with impairments in cognition, especially learning and memory. However, major individual differences are known to exist. Using the classical Morris Water Maze (MWM) task, we discriminated a population of 24-months old Long Evans aged rats in two groups - memory-impaired (AI) and memory-unimpaired (AU) in comparison with 6-months old adult animals. AI rats presented deficits in learning, reverse memory and retention. At the molecular level, an increase in metabotropic glutamate receptors 5 (mGluR5) was observed in post-synaptic densities (PSD) in the hippocampus of AU rats after training. Scaffolding Homer 1b/c proteins binding to group 1 mGluR facilitate coupling with its signaling effectors while Homer 1a reduces it. Both Homer 1a and 1b/c levels were up-regulated in the hippocampus PSD of AU animals following MWM task. Using immunohistochemistry we further demonstrated that mGluR5 as well as Homer 1b/c stainings were enhanced in the CA1 hippocampus sub-field of AU animals. In fact mGluR5 and Homer 1 isoforms were more abundant and co-localized in the hippocampal dendrites in AU rats. However, the ratio of Homer 1a/Homer 1b/c bound to mGluR5 in the PSD was four times lower for AU animals compared to AI rats. Consequently, AU animals presented higher PKCγ, ERK, p70S6K, mTOR and CREB activation. Finally the expression of immediate early gene Arc/Arg3.1 was shown to be higher in AU rats in accordance with its role in spatial memory consolidation. On the basis of these results, a model of successful cognitive aging with a critical role for mGluR5, Homer 1 proteins and downstream signalling pathways is proposed here