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• Tau pathology disrupts cerebral blood supply and blood–brain barrier integrity. • Neurodegeneration and endothelial dysfunction worsen with microgliosis, astrogliosis. • The neurovascular unit is key in inflammation and neuronal excitotoxicity. • Heparan sulfate and LRP1 aid tau trafficking, causing mitochondrial dysfunction. • Toxic oligomers reduce synaptic plasticity and function in Alzheimer's disease. Alzheimer's disease is a fatal chronic neurodegenerative condition marked by a gradual decline in cognitive abilities and impaired vascular function within the central nervous system. This affliction initiates its insidious progression with the accumulation of two aberrant protein entities including Aβ plaques and neurofibrillary tangles. These chronic elements target distinct brain regions, steadily erasing the functionality of the hippocampus and triggering the erosion of memory and neuronal integrity. Several assumptions are anticipated for AD as genetic alterations, the occurrence of Aβ plaques, altered processing of amyloid precursor protein, mitochondrial damage, and discrepancy of neurotropic factors. In addition to Aβ oligomers, the deposition of tau hyper-phosphorylates also plays an indispensable part in AD etiology. The brain comprises a complex network of capillaries that is crucial for maintaining proper function. Tau is expressed in cerebral blood vessels, where it helps to regulate blood flow and sustain the blood–brain barrier's integrity. In AD, tau pathology can disrupt cerebral blood supply and deteriorate the BBB, leading to neuronal neurodegeneration. Neuroinflammation, deficits in the microvasculature and endothelial functions, and Aβ deposition are characteristically detected in the initial phases of AD. These variations trigger neuronal malfunction and cognitive impairment. Intracellular tau accumulation in microglia and astrocytes triggers deleterious effects on the integrity of endothelium and cerebral blood supply resulting in further advancement of the ailment and cerebral instability. In this review, we will discuss the impact of tau on neurovascular impairment, mitochondrial dysfunction, oxidative stress, and the role of hyperphosphorylated tau in neuron excitotoxicity and inflammation. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a pregnancy complication associated with multi-organ damage and vascular dysfunction. Meanwhile, microRNAs or miRNAs are crucial regulators of gene expression in various diseases including PE. Our previous studies reported high expression of miR-510 in the PE patients' blood compared to normal. Hence, we hypothesize that miR-510-3p targets Vascular endothelial growth factor A (VEGFA) in the regulation of PI3K/AKT/eNOS/mTOR axis in PE and miR-510-3p could be a potential therapeutic target for PE. The proliferation, migration, and apoptosis of HTR8/SVNeo and BeWo cells were analyzed by manipulating the miR-510-3p and VEGFA expression. Similarly, the inhibition of miR-510-3p through anti-miR-510-3p was analyzed in PE rat models, and the biochemical, hemodynamic parameters, and histopathology were examined between the groups. Moreover, the expression of miR-510-3p and VEGFA/PI3K/AKT/eNOS/mTOR axis was analyzed using qRT-PCR and Western blot. Significant changes were observed in the BP, proteinuria, and other biochemical parameters between PE and control rats. Our results suggest that miR-510-3p targets VEGFA leading to vascular dysfunction in PE, while treatment with anti-miR-510-3p in the PE-induced rat model exhibits a significant change in the expression of miR-510-3p/VEGFA/PI3K/AKT/eNOS/mTOR signaling where miR-510-3p showed lesser expression and vice versa with VEGFA. The gene and protein expression analysis revealed a significant correlation between miR-510-3p and the VEGFA signaling axis in PE. Thus, our findings from in vitro and in vivo suggest miR-510-3p as a potential therapeutic target and anti-miR-510-3p as a novel therapeutic molecule for PE. • We hypothesize that miR-510-3p targets Vascular endothelial growth factor A (VEGFA). • We identify the regulation of PI3K/AKT/eNOS/mTOR axis via VEGFA in preeclampsia. • We elucidate if miR-510-3p could be a potential therapeutic target for preeclampsia. • Results suggest that miR-510-3p targets VEGFA leading to vascular dysfunction in PE. • Treatment with anti-miR-510-3p exhibits a significant reduction in disease condition. [ABSTRACT FROM AUTHOR]

• In a population of non-institutionalized 75 years-old subjects, lncRNA H19 predicts all-cause mortality over a follow-up of 14 years. • lncRNA H19 is differentially expressed in males and females, and it is a possible feature of sex differences in lifespan. • low-levels of lncRNA NKILA are associated with an increased risk of lacunar stroke, detected by magnetic resonance, over a follow-up of 7.5 years. Differential expression of long non-coding RNAs (lncRNAs) is a hallmark of cardiovascular aging, cerebrovascular diseases, and neurodegenerative disorders. This research article investigates the association between a panel of lncRNAs and the risk of death and ischemic stroke in a cohort of non-institutionalized elderly subjects. A total of 361 healthy individuals aged 75 years old, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included. Expression of lncRNAs at baseline was assessed using quantitative polymerase chain reaction PCR with pre-amplification reaction, using 18S for normalization. The primary endpoint was all-cause mortality; the secondary endpoint was the incidence of new ischemic brain lesions. Death was assessed over a 14-year follow-up, and ischemic brain lesions were evaluated by magnetic resonance imaging (MRI) over a 90-month follow-up. Ischemic brain lesions were divided into large brain infarcts (Ø ≥ 1.5 cm) or lacunes (Ø < 1.5 cm) The primary endpoint occurred in 53.5 % of the study population. The incidence of the secondary endpoint was 16 %, with a 3.3 % being large brain infarcts, and a 12.7 % lacunes. After adjustment for potential confounders, the lncRNA H19 predicted the incidence of the primary endpoint (HR 1.194, 95 % C.I. 1.012–1.409, p = 0.036), whereas the lncRNA NKILA was associated with lacunar stroke (HR 0.571, 95 % C.I. 0.375–0.868, p = 0.006). In a prospective cohort of non-institutionalized elderly subjects, high levels of lncRNA H19 are associated with a higher risk of death, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

Systemic Sclerosis (SSc) is an autoimmune disease characterized by vascular and immune system dysfunction, along with tissue fibrosis. Our previous study found GRB2 was downregulated by salvianolic acid B, a small molecule drug that attenuated skin fibrosis of SSc. Here we aim to investigate the role of GRB2 in SSc. The microarray data of SSc skin biopsies in Caucasians were obtained from the Gene Expression Omnibus (GEO) database. The expression of GRB2 was further detected in Chinese SSc and healthy controls. Bleomycin (BLM)-induced skin fibrosis mice were used to explore how GRB2 downregulation affected fibrosis. The apoptosis of EA.hy926 endothelial cells was induced by H 2 O 2 and apoptosis ratio was measured by flow cytometric. Transcriptome and phosphoproteomic analyses were performed to explore the regulated pathway. The expression of GRB2 was significantly enhanced in SSc patient skin, 1.51-fold in Caucasians and 1.40-fold in Chinese. Double immunofluorescence staining showed the endothelial cells of SSc patient's skin highly expressed GRB2. The in vivo study revealed that GRB2 knockdown alleviated skin fibrosis and apoptosis of endothelial cells in BLM mouse skin. The in vitro study showed that GRB2 downregulation inhibited the apoptosis of EA.hy926 and protected them from H 2 O 2 -induced hyperpermeability. Moreover, transcriptome and phosphoproteomic analysis suggested the focal adhesion pathway was enriched in GRB2 siRNA transfected endothelial cells. Our results demonstrated GRB2 highly expressed in endothelial cells of SSc skin, and inhibiting GRB2 could effectively attenuate BLM-induced skin fibrosis and endothelial cell apoptosis. GRB2 is expected to be a new therapeutic target for SSc. • Enhanced GRB2 in SSc patient skin, 1.51-fold in Caucasians and 1.40-fold in Chinese. • The endothelial cells of SSc patient skin highly expressed GRB2. • Inhibiting GRB2 attenuated BLM-induced skin fibrosis and endothelial cell apoptosis. • Inhibiting GRB2 protected EA.hy926 from apoptosis and H 2 O 2 -induced hyperpermeability. • Focal adhesion pathway was regulated by GRB2 to influence endothelial cell apoptosis. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome is a syndrome of acute heart failure due to left ventricular systolic dysfunction that is associated with increased cardiovascular morbidity and mortality. It occurs in both sexes and at all ages, but predominates in post-menopausal women for reasons that are unclear. In a patient who presents with cardiac symptoms, electrocardiographic changes, and/or biomarker elevation indicating myocardial stress (i.e. troponin elevation), this condition should be considered in the differential diagnosis. Cardiac imaging is critical for a timely diagnosis of this condition and has management implications. This syndrome can occur with or without underlying coronary artery disease, and while there are various characteristic myocardial patterns described on imaging, the most common one is left ventricular dysfunction due to apical stunning with basal hyperkinesis. In the acute phase, Takotsubo syndrome can lead to life-threatening sequelae, including cardiogenic shock, pulmonary edema, thromboembolism, and arrhythmias. Multiple pathophysiologic mechanisms are implicated, including an acute increase in left ventricular afterload in the setting of sympathetic activation with a catecholamine storm, multi-vessel coronary vasospasm, coronary endothelial microvascular dysfunction, and inflammation. In this review, we discuss the current knowledge surrounding presentation, diagnosis, and treatment of this under-diagnosed condition. [ABSTRACT FROM AUTHOR]

The gut microbial metabolite trimethylamine N-oxide (TMAO) is regarded as a novel risk factor for hypertension. Berberine (BBR) exerts cardiovascular protective effects by regulating the gut microbiota-metabolite production pathway. However, whether and how BBR alleviates TMAO-induced vascular dysfunction in hypertension remains unclear. In the present study, we observed that plasma TMAO and related bacterial abundance were significantly elevated and negatively correlated with vascular function in 86 hypertensive patients compared with 46 normotensive controls. TMAO activated endoplasmic reticulum stress (ERS) signaling pathway to promote endothelial cell dysfunction and apoptosis in vitro. BBR (100, 200 mg · kg−1 ·d−1) for 4 weeks ameliorates TMAO-induced vascular dysfunction and ERS activation in a choline-angiotensin II hypertensive mouse model. We found that plasma TMAO levels in 15 hypertensive patients treated with BBR (0.4 g, tid) were reduced by 8.8 % and 16.7 % at months 1 and 3, respectively, compared with pretreatment baseline. The oral BBR treatment also improved vascular function and lowered blood pressure. Faecal 16 S rDNA showed that BBR altered the gut bacterial composition and reduced the abundance of CutC/D bacteria in hypertensive mice and patients. In vitro bacterial cultures and enzyme reaction systems indicated that BBR inhibited the biosynthesis of TMAO precursor in the gut microbiota by binding to and inhibiting the activity of CutC/D enzyme. Our results indicate that BBR improve vascular dysfunction at least partially by decreasing TMAO via regulation of the gut microbiota in hypertension. [Display omitted] • Circulating TMAO and related bacterial abundance were elevated and associated with vascular dysfunction in hypertension. • TMAO activated endoplasmic reticulum stress to promote endothelial cell dysfunction and apoptosis. • BBR reduced plasma TMAO by decreasing abundance of CutC/D bacteria and inhibiting CutC/D enzyme activity in gut microbiota. • BBR had a protective effect against TMAO-induced vascular dysfunction and endoplasmic reticulum stress activation in hypertension. [ABSTRACT FROM AUTHOR]

Perinatal HIV infection (PHIV) and prolonged use of antiretroviral therapy (ART) may increase the likelihood of developing subclinical vascular dysfunction at an early age. We conducted a systematic review to assess the effect of PHIV and ART on intima-media thickness (IMT), arterial stiffness and endothelial function in individuals aged 6–25 years. Medline, Embase and Web of Science were searched, and studies screened by two independent reviewers. We performed a meta-analysis on selected studies reporting on IMT. A total of 680 studies were retrieved from the databases, with 21 studies deemed eligible for qualitative analysis. There were few studies assessing IMT, arterial stiffness and endothelial function. More than half of the studies found either increased IMT, stiffer arteries or impaired endothelial function in PHIV compared to uninfected controls. A minority of the studies reported that the two groups had similar vascular parameters, a conflicting finding. There was a lack of standardisation for IMT assessment and reporting in numerous studies. In a meta-analysis of seven studies with matching methodologies, IMT was higher in PHIV compared to uninfected controls, (mean difference, 0.05 (0.01–0.09; p = 0.01) but heterogeneity between the studies was substantial (I2, 96.7%; p < 0.001). PHIV may affect vascular structure and function. Existing studies are generally small, often contradictory, and predominantly cross-sectional in design. Further studies are required to understand vascular health in PHIV to identify cardiovascular disease risk and improve interventional strategies aimed at prevention and treatment of early vascular changes in this population. [Display omitted] • HIV infection and antiretroviral therapy (ART) may accelerate subclinical vascular damage and atherogenesis. • Young people with perinatal HIV have altered vascular structure and function. • Presently, data on perinatal HIV (PHIV) and atherogenesis are limited and sometimes contradictory, hence further studies are warranted. • The role of ART in vascular dysfunction remains unclear. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) is a prevalent cardiovascular disease. The main hallmarks of this condition are atherosclerosis and myopathy in the lower limbs, with progressive deterioration of the functional capacity and quality of life of affected individuals. There is evidence supporting physical exercise as an effective alternative for the treatment of PAD. In this context, unraveling the biological mechanisms by which exercise intervention might improve the clinical manifestation of PAD can help gain insight into the pathophysiology of this condition, as well as explore new treatment and preventive approaches. In this review, we thus describe the different mechanisms by which exercise could impact the different hallmarks of PAD. Physical exercise positively modulates pathways related to inflammation and the atherosclerotic process and can attenuate the progression of lower-limb myopathy, with subsequent improvements in patients' functional capacity and health-related quality of life. At the whole-body level, these improvements translate into a better functional status and wellbeing. [Display omitted] • Exercise positively modulates the mechanisms related to inflammation and vascular endothelial dysfunction involved in peripheral arterial disease (PAD). • Physical exercise attenuates myopathy progression in lower-limb muscles in PAD. • Aforementioned improvements translate into a better functional status and HRQoL in patients with PAD. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is characterized by insulin resistance, hyperglycemia, excessive fat accumulation and dyslipidemia, and is known to be accompanied by neuropathological symptoms such as memory loss, anxiety, and depression. As the number of MetS patients is rapidly increasing globally, studies on the mechanisms of metabolic imbalance-related neuropathology are emerging as an important issue. Ca2+/calmodulin-dependent kinase II (CaMKII) is the main Ca2+ sensor and contributes to diverse intracellular signaling in peripheral organs and the central nervous system (CNS). CaMKII exerts diverse functions in cells, related to mechanisms such as RNA splicing, reactive oxygen species (ROS) generation, cytoskeleton, and protein-protein interactions. In the CNS, CaMKII regulates vascular function, neuronal circuits, neurotransmission, synaptic plasticity, amyloid beta toxicity, lipid metabolism, and mitochondrial function. Here, we review recent evidence for the role of CaMKII in neuropathologic issues associated with metabolic disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA). Resistin is an adipokine that induces adipose tissue inflammation and activation of monocytes/macrophages via adenylate cyclase-associated protein-1 (CAP1). Resistin levels are increased in RA and might cause perivascular adipose tissue (PVAT) dysfunction, leading to vascular damage and CVD. This study aimed to investigate the role of resistin in promoting PVAT dysfunction by increasing local macrophage and inflammatory cytokines content in antigen-induced arthritis (AIA). Resistin pharmacological effects were assessed by using C57Bl/6J wild-type (WT) mice, humanized resistin mice expressing human resistin in monocytes-macrophages (hRTN+/-/-), and resistin knockout mice (RTN-/-) with AIA and respective controls. We investigated AIA disease activity and functional, cellular, and molecular parameters of the PVAT. Resistin did not contribute to AIA disease activity and its concentrations were augmented in the PVAT and plasma of WT AIA and hRTN+/-/- AIA animals. In vitro exposure of murine arteries to resistin impaired vascular function by decreasing the anti-contractile effect of PVAT. WT AIA mice and hRTN+/-/- AIA mice exhibited PVAT dysfunction and knockdown of resistin prevented it. Macrophage-derived cytokines, markers of types 1 and 2 macrophages, and CAP1 expression were increased in the PVAT of resistin humanized mice with AIA, but not in knockout mice for resistin. This study reveals that macrophage-derived resistin promotes PVAT inflammation and dysfunction regardless of AIA disease activity. Resistin might represent a translational target to reduce RA-driven vascular dysfunction and CVD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Long-term DBP exposure alters expression of nine genes in EA.hy926 cells. • Long-term DBP exposure affects extracellular matrix, cell and focal adhesions. • Long-term DBP exposure associates with ten human diseases with vascular etiology. • Top three categories: cardiovascular, cerebrovascular, and immune system diseases. General population is exposed to dibutyl phthalate (DBP) through continuous use of various consumer products. DBP exhibits its effects mainly on the endocrine and reproductive system but it can also affect the function of the vasculature; however, the underlying mechanisms behind DBP-induced vascular dysfunction are not fully understood. To infer pathways, molecular functions, biological processes, and human diseases associated with DBP exposure, we integrated the toxicogenomic data obtained from the 4-week-long exposure of human vascular endothelial cells (ECs) to three environmentally relevant concentrations of DBP with the in silico analysis. Nine genes were affected by DBP exposure: six of the integrin family, VCAM1 , ICAM1 , and MMP2. As shown by the in silico analysis, changes in DBP-affected genes could affect extracellular matrix and binding of molecules and cells to ECs, thereby altering cell adhesion and migration. Several pathways, molecular functions, and biological processes were further identified to provide insight into the DBP-vascular disease relationships and the potential mechanism of action. The top three human disease categories associated with DBP exposure and vascular dysfunction include cardiovascular, cerebrovascular, and immune system diseases. Integration of experimental and in silico approaches may offer better understanding of the potential human health risks associated with DBP exposure. [ABSTRACT FROM AUTHOR]

Background and Aims: Glycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results.Methods and Results: We investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8-47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients.Conclusion: Our data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients. [ABSTRACT FROM AUTHOR]

Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodilation was affected in both arteries in a different way. The aorta from MetS showed vascular dysfunction, including lower response to acetylcholine and sodium nitroprusside, while the renal artery from MetS presented a preserved relaxation to acetylcholine and an increased sensitivity to sodium nitroprusside. We did not find vascular oxidative stress in the aorta from MetS, but we found a significant decrease in PPARγ, phospho-Akt (p-Akt) and phospho-eNOS (p-eNOS) protein expression. On the other hand, we found oxidative stress in the renal artery from MetS, and PPARγ, Akt and p-Akt were overexpressed. No evidence of atherosclerosis was found in arteries from MetS. MetS affects vascular function differently depending on the vessel. In the aorta, it decreases both the vasodilation and the expression of the PPARγ/Akt/eNOS pathway, while in the renal artery, it increases the expression of PPARγ/Akt signalling pathway without decreasing the vasodilation. [Display omitted] • Metabolic syndrome (MetS) decreases endothelium-dependent and -independent vasodilation in the aorta. • MetS triggers vasodilator compensatory mechanisms in the renal artery even in the presence of oxidative stress. • PPARγ/Akt/eNOS pathway is downregulated in the aorta by MetS. • PPARγ/Akt signalling pathway is overexpressed in the renal artery by MetS. [ABSTRACT FROM AUTHOR]

• Omentin-1 serves as a novel biomarker for predicting the functional outcome of acute ischemic stroke, and low circulating omentin-1 level indicates high risk of ischemic stroke. • Elevated omentin-1 level could attenuate atherosclerosis and exert a favorable impact on cerebral ischemia. • Omentin-1 has benefical effects on vascular inflammation and dysfunction through various signaling pathways. • Metformin and statins together with omentin-1 have great potential to be developed into novel drug therapy against ischemic stroke. Omentin-1, a newly identified adipokine, has recently been revealed as a novel biomarker for ischemic stroke (IS). Low circulating omentin-1 levels could indicate a high risk of IS, and elevated omentin-1 levels exert a favorable impact on cerebral ischemia. Furthermore, omentin-1 has anti-atherosclerotic, anti-inflammatory, and cardiovascular protective capabilities through the intracellular Akt/AMP-activated protein kinase (AMPK)/ nuclear factor-κB (NF-κB) and certain protein kinase (ERK, JNK, and p38) signaling pathways. Omentin-1 also alleviates endothelial cell dysfunction, improves revascularization via the Akt-endothelial nitric-oxide synthase (eNOS) regulatory axis, promotes endothelium-dependent vasodilation through endothelium-derived NO in an eNOS fashion, and inhibits VSMC proliferation by means of AMPK/ERK signaling pathways, VSMC migration via inactivation of the NADPH oxidase (NOX)/ROS/p38/HSP27 pathways and artery calcification via the PI3K-Akt pathway. These findings indicate that omentin-1 may be a negative mediator of IS. Pharmacologically, several lines of clinical evidence indicate that metformin and statins could elevate omentin-1 levels, although the specific mechanism has not been precisely delineated until now. This study is the first to summarize the comprehensive mechanisms between omentin-1 and atherosclerosis and to review the shielding effect of omentin-1 on IS. We shed light on omentin-1 as a novel therapeutic target for combating IS. [ABSTRACT FROM AUTHOR]

[Display omitted] Emerging evidence suggests that vascular pathological changes play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The dysfunction of the cerebral vasculature occurs in the early course of AD, characterized by alterations in vascular morphology, diminished cerebral blood flow (CBF), impairment of the neurovascular unit (NVU), vasculature inflammation, and cerebral amyloid angiopathy. Vascular dysfunction not only facilitates the influx of neurotoxic substances into the brain, triggering inflammation and immune responses but also hampers the efflux of toxic proteins such as Aβ from the brain, thereby contributing to neurodegenerative changes in AD. Furthermore, these vascular changes significantly impact drug delivery and distribution within the brain. Therefore, developing targeted delivery systems or therapeutic strategies based on vascular alterations may potentially represent a novel breakthrough in AD treatment. This review comprehensively examines various aspects of vascular alterations in AD and outlines the current interactions between nanoparticles and pathological changes of vascular. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia is one of the main risk factors associated with atherosclerosis and cardiovascular disease, the leading cause of death worldwide. During pregnancy, maternal hypercholesterolemia develops, and it can occur in a physiological (MPH) or supraphysiological (MSPH) manner, where MSPH is associated with endothelial dysfunction and early atherosclerotic lesions in the fetoplacental vasculature. In the pathogenesis of atherosclerosis, endothelial activation and endothelial dysfunction, characterized by an imbalance in the bioavailability of nitric oxide, contribute to the early stages of this disease. Macrophages conversion to foam cells, cholesterol efflux from these cells and its differentiation into a pro- or anti-inflammatory phenotype are also important processes that contribute to atherosclerosis. In adults it has been reported that native and modified HDL and LDL play an important role in endothelial and macrophage function. In this review it is proposed that fetal lipoproteins could be also relevant factors involved in the detrimental vascular effects described in MSPH. Changes in the composition and function of neonatal lipoproteins compared to adults has been reported and, although in MSPH pregnancies the fetal lipid profile does not differ from MPH, differences in the lipidomic profiles of umbilical venous blood have been reported, which could have implications in the vascular function. In this review we summarize the available information regarding the effects of lipoproteins on endothelial and macrophage function, emphasizing its possible implications on fetal adverse outcomes associated to maternal hypercholesterolemia during pregnancy. [ABSTRACT FROM AUTHOR]

Due to their short half-lives, repeated administration of anti-hyperglycemic drugs can cause pain, discomfort, tissue damage, and infection in diabetic patients. Therefore, there is a need to develop long-term drug delivery systems to treat diabetes and its complications. C-peptide can prevent diabetic complications, including diabetic vasculopathy, but its clinical application is limited by its short half-life. Here, we developed K9-C-peptide (human C-peptide conjugated to an elastin-like biopolymer) and investigated its long-term influence on hyperglycemia-induced vascular dysfunction using an aortic endothelium model in diabetic mice. Using pharmacokinetics and in vivo imaging, we found that subcutaneously injected K9-C-peptide formed a hydrogel depot that slowly released human C-peptide into the blood circulation for 19 days. Administration of K9-C-peptide, human C-peptide, or K8 polypeptide had no effect on body weight or blood glucose levels. The slow release of C-peptide from K9-C-peptide hydrogels provided prolonged prevention of oxidative stress, inflammatory responses, and endothelial apoptosis in a hyperglycemia-induced vascular dysfunction model using the diabetic mouse aorta. Subcutaneous administration of unbound human C-peptide and K8 polypeptide were used as negative controls and had no effects. These results suggest that K9-C-peptide is suitable for the long-term delivery of human C-peptide for treating vascular dysfunction in diabetic patients. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• Exposure to 1 mg/kg of Cd for 14 days induced hypertension • Exposure to 1 mg/kg of Cd for 14 days induced vascular dysfunction in MRA and aorta. • All vascular changes were accompanied by an increased ROS production • Cd exposure activates NADPH oxidase, RAS and COX-2 pathway Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin–angiotensin system and COX2 pathway activation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, the leading cause of dementia in the elderly, is a neurodegenerative condition characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, age-related vascular changes accompany or even precede the development of Alzheimer's pathology, raising the possibility that they may have a pathogenic role. This review provides an appraisal of the alterations in cerebral and systemic vasculature, the heart, and hemostasis that occur in Alzheimer's disease and their relationships to cognitive impairment. Although the molecular pathogenesis of these alterations remains to be defined, amyloid-β is a likely contributor in the brain as in the heart. Collectively, the evidence suggests that vascular pathology is a likely pathogenic contributor to age-related dementia, including Alzheimer's disease, inextricably linked to disease onset and progression. Consequently, the contribution of vascular factors should be considered in preventive, diagnostic, and therapeutic approaches to address one of the major health challenges of our time. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) is a gasotransmitter implied in metabolic diseases, insulin resistance, obesity, and type 2 Diabetes Mellitus. This study aimed to determine the effect of chronic administration of sodium hydrosulfide (NaHS; inorganic H 2 S donor), L-Cysteine (L-Cys; substrate of H 2 S producing enzymes) and DL-Propargylglycine (DL-PAG; cystathionine-gamma-lyase inhibitor) on the vascular dysfunction induced by insulin resistance in rat thoracic aorta. For this purpose, 72 animals were divided into two main sets that received: 1) tap water (control group; n = 12); and 2) fructose 15% w/v in drinking water [insulin resistance group (IR); n = 60] for 20 weeks. After 16 weeks, the group 2 was divided into five subgroups (n = 12 each), which received daily i. p. injections during 4 weeks of: 1) non-treatment (control); 2) vehicle (phosphate buffer saline; PBS, 1 ml/kg); 3) NaHS (5.6 mg/kg); 4) L-Cys (300 mg/kg); and (5) DL-PAG (10 mg/kg). Hemodynamic variables, metabolic variables, vascular function, ROS levels and the expression of p-eNOS and eNOS were determined. IR induced: 1) hyperinsulinemia; 2) increased HOMA-index; 3) decreased Matsuda index; 4) hypertension, vascular dysfunction, increased ROS levels; 5) increased iNOS, and 6) decreased CSE, p-eNOS and eNOS expression. Furthermore, IR did not affect contractile responses to norepinephrine. Interestingly, NaHS and L-Cys treatment, reversed IR-induced impairments and DL-PAG treatment decreased and increased the HOMA and Matsuda index, respectively. Taken together, these results suggest that NaHS and L-Cys decrease the metabolic and vascular alterations induced by insulin resistance by reducing oxidative stress and activating eNOS. Thus, hydrogen sulfide may have a therapeutic application. [Display omitted] [ABSTRACT FROM AUTHOR]

Renin-angiotensin (Ang II)-aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS). Male C57/BL6J or mt-keima mice (6–8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg/day). Ethanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1α (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mt-keima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H 2 O 2 bioavailability. These responses were prevented by losartan. AT 1 receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H 2 O 2 bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking. [Display omitted] ● Chronic ethanol consumption activates RAAS and triggers vascular dysfunction. ● RAAS impairs mitochondrial quality in the vasculature. ● Chronic ethanol induces mitochondrial ROS formation and decreases NO and H 2 O 2. ● AT1R blockers protect from chronic ethanol consumption-induced vascular dysfunction. [ABSTRACT FROM AUTHOR]

In preeclampsia, vasospasm, oxidative stress, endothelial dysfunction, and immune dysregulation are key mediators of maternal disease. A new time-of-disease treatment is needed with the potential to treat these areas of pathophysiology. A review of the literature has indicated that metabolites of the kynurenine pathway have the potential to; (i) induce vasorelaxation of resistance arteries and reduce blood pressure; (ii) exert antioxidant effects and reduce the effects of poly-ADP ribose polymerase activation (iii) prevent endothelial dysfunction and promote endothelial nitric oxide production; (iv) cause T cell differentiation into tolerogenic regulatory T cells and induce apoptosis of pro-inflammatory Th1 cells. This has led to the hypothesis that increasing Kynurenine pathway activity may offer a new treatment strategy for preeclampsia. • Vascular dysfunction, oxidative stress and immune dysregulation drive maternal preeclampsia. • Kynurenine causes vasorelaxation, counteracts oxidative stress and induces immunotolerance • We postulate increasing Kynurenine pathway activity may ameliorate drivers of maternal disease. • Extensive pre-clinical proof-of-principle and safety experiments will precede human treatment. [ABSTRACT FROM AUTHOR]

Objectives: To understand the pathophysiology of cardiovascular (CV) dysfunction in rheumatoid arthritis (RA) is crucial, but limited by the paucity of animal models able to mimic CV impairments. We wanted to determine if the rat model of Pristane-Induced Arthritis (PIA) reproduced cardiometabolic impairments of RA.Methods: Dark Agouti rats received an injection of pristane or saline (controls) at day 0. Reactivity to vasoconstrictors and vasodilators was studied in aortic rings and mesenteric arteries at day 28 (acute) and day 120 post-induction (chronic phase). Circulating markers of inflammation, lipid and glucose levels, arthritis and radiographic scores were assessed.Results: In aortic rings, PIA induced a reduced vasoconstriction to phenylephrine and serotonin in both phases of the model. The relaxant effect of acetylcholine was decreased in PIA in acute (P < 0.05) but not in chronic phase. In mesenteric arteries, only the acetylcholine-induced vasorelaxation was impaired in PIA rats in the chronic phase (P < 0.001). Serum interleukin-6 levels were higher, total cholesterol and triglycerides levels were lower in PIA in both phases (P < 0.001) whereas myeloperoxidase activity and blood glucose were unchanged. Adiponectine levels were lower in PIA in acute (P < 0.001) but not in chronic phase. Endothelial function correlated with interleukin-6, total cholesterol levels and arthritis score in aorta but not in mesenteric arteries.Conclusions: As new information, PIA induces endothelial dysfunction in micro-/macro-vascular beds and low lipid levels, like in RA. This model of chronic arthritis might be useful to study CV pathophysiology and to screen new therapeutic options for reducing CV risk in RA. [ABSTRACT FROM AUTHOR]

Obesity is associated with innumerous comorbidities, including cardiovascular diseases, that occur by various mechanisms, including hyperactivation of the renin angiotensin system, oxidative stress and cardiovascular overload. Postnatal early overfeeding (PO) leads to metabolic imprinting that induces weight gain throughout life, and in this paper, we aimed to evaluate cardiovascular parameters and cardiac molecular changes due to obesity induced early in life by PO. Male Wistar rats (120-days-old), raised in normal (NL) or small litters (SL), were submitted to cardiac assessment by transthoracic echocardiography and blood pressure evaluation. Thereafter, the hearts and aorta rings from these animals were submitted to ex-vivo isolated assays. Still, cardiac morphological and molecular analyses were performed. PO induced ventricular hypertrophy, raised blood pressure, increased fibrosis, and ex-vivo cardiac dysfunction in the SL group. Furthermore, SL animals presented impaired vascular relaxation and increased vascular constriction responses. Besides functional alterations, SL animals presented augmented RAB-1b and SOD-1, despite no changes in RAS receptors expression or Akt/eNOS pathway. Taken together, our results consolidate the knowledge that the PO during lactation is critical for cardiometabolic programming, leading to oxidative stress and cardiac remodeling in later stages of life. [ABSTRACT FROM AUTHOR]

Adverse pregnancy outcomes (APOs)-including pre-term birth, pre-eclampsia, and intrauterine growth restriction-are common interrelated disorders caused by placental dysfunction and maternal vascular abnormalities (endothelial activation, inflammation, and vasospasm) that occur in approximately 10% to 20% of pregnancies. Women who experience APOs are at increased risk for future cardiovascular disease (CVD). APOs are associated with increased risk of development of hypertension, left ventricular hypertrophy/dysfunction, vascular dysfunction, and renal dysfunction. The vascular abnormalities that are present during an APO also underlie common, difficult-to-treat forms of CVD in women as they age (e.g., cardiac microvascular dysfunction, heart failure with preserved ejection fraction), suggesting shared mechanistic pathways for APOs and CVD. Here, the authors synthesize the current information and knowledge gaps regarding the progression from APO to CVD. Understanding the risk factors for and pathogenesis of APO-related cardiovascular dysfunction is a critical unmet need that could inform efforts to prevent and more effectively treat CVD in women. [ABSTRACT FROM AUTHOR]

Abstract Atherosclerosis is the primary underlying cause of myocardial infarction, ischemic stroke, and peripheral artery disease. The disease preferentially occurs in arterial regions exposed to disturbed blood flow, in part, by altering expression of flow-sensitive coding- and non-coding genes. In this review, we summarize the role of noncoding RNAs, [microRNAs (miRNAs) and long noncoding RNAs(lncRNAs)], as regulators of gene expression and outline their relationship to the pathogenesis of atherosclerosis. While miRNAs are small noncoding genes that post-transcriptionally regulate gene expression by targeting mRNA transcripts, the lncRNAs regulate gene expression by diverse mechanisms, which are still emerging and incompletely understood. We focused on multiple flow-sensitive miRNAs such as, miR-10a, -19a, -23b, -17~92, -21, -663, -92a, -143/145, -101, -126, -712, -205, and -155 that play a critical role in endothelial function and atherosclerosis by targeting inflammation, cell cycle, proliferation, migration, apoptosis, and nitric oxide signaling. Flow-dependent regulation of lncRNAs is just emerging, and their role in vascular dysfunction and atherosclerosis is unknown. Here, we discuss the flow-sensitive lncRNA STEEL along with other lncRNAs studied in the context of vascular pathophysiology and atherosclerosis such as MALAT1, MIAT1, ANRIL, MYOSLID, MEG3, SENCR, SMILR, LISPR1, and H19. Also discussed is the use of these noncoding RNAs as potential biomarkers and therapeutics to reduce and regress atherosclerosis. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Background: Enhancing relaxation of resistance arteries and decreasing oxidative stress by using natural products are potential strategies for prevention and treatment of hypertension.Purpose: This study investigated whether aqueous extract of Moringa oleifera leaves (MOE) could alleviate Nω-nitro-L-arginine-methyl ester (L-NAME)-induced high blood pressure via modulation of vascular function and antioxidant properties.Methods: An experimental hypertensive model was established by administration of L-NAME (50 mg/kg/day) in drinking water to male Wistar rats for 3 weeks. Arterial pressure was measured indirectly by tail-cuff plethysmography and directly via femoral artery catheterization. Vasoreactivity of isolated rat mesenteric arterial bed was determined by the changes in perfusion pressure detected by a pressure transducer. Vascular superoxide anion (O2•-) production was determined by lucigenin-enhanced chemiluminescence. Other biochemical measurements including malondialdehyde (MDA) level, superoxide dismutase (SOD), and catalase (CAT) activities were measured by colorimetric assay.Results: L-NAME-treated rats developed significantly increased blood pressure and heart rate. Concurrent oral treatment with MOE (30 and 60 mg/kg/day) could decrease the high blood pressure and tachycardia in a dose-dependent manner. MOE reduced the impairment of acetylcholine-induced relaxation and decreased the hyperreactivity of adrenergic-mediated contraction in response to periarterial nerve stimulation and phenylephrine in isolated mesenteric arterial beds. In addition, MOE exhibited antioxidant effects in the hypertensive rats, as indicated by suppression of vascular O2•- production, decrease of plasma and thoracic aorta MDA levels, and increase of antioxidant activities of SOD and CAT. Moreover, MOE (0.001-0.3 mg) produced a dose-dependent relaxation in methoxamine pre-contracted arterial beds isolated from L-NAME hypertensive rats, which was abolished by endothelium denudation.Conclusion: These findings suggest that the antihypertensive effect of MOE in L-NAME-hypertensive rats may be mediated by alleviating vascular dysfunction and oxidative stress and promoting endothelium-dependent vasorelaxation. MOE may be potentially useful as a natural product against hypertension. [ABSTRACT FROM AUTHOR]

Abstract Hypertension has complex vascular pathogenesis and therefore the molecular etiology remains poorly elucidated. Endoplasmic reticulum stress (ERS), which is a condition of the unfolded/misfolded protein accumulation in the endoplasmic reticulum, has been defined as a potential target for cardiovascular disease. In the present study, the effects of ERS inhibition on hypertension-induced alterations in the vessels were investigated. In male Wistar albino rats, hypertension was induced through unilateral nephrectomy, deoxycorticosterone-acetate (DOCA) injection (20 mg/kg, twice a week) and 1% NaCl with 0.2% KCI added to drinking water for 12 weeks. An ERS inhibitor, tauroursodeoxycolic acid (TUDCA) (150 mg/kg/day, i.p.), was administered for the final four weeks. ERS inhibition in DOCA-salt induced hypertension was observed to have reduced systolic blood pressure, improved endothelial dysfunction, enhanced plasma nitric oxide (NO) level, reduced protein expressions of phosphorylated-double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (pPERK), 78 kDa glucose-regulated protein (GRP78), Inositol trisphosphate receptor1 (IP 3 R1) and Epidermal growth factor receptor (EGFR), increased expressions of endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and B cell lymphoma2 (Bcl2) in vessels. These findings suggest that the beneficial effects of ERS inhibition on hypertension may be related to protection of vessel functions through restoration of endoplasmic reticulum calcium homeostasis, and apoptotic and mitotic pathways. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract Aims The interleukin-10 (IL-10) is an immuno-regulatory cytokine that plays a protective effect in the vasculature. IL-10 binding to its receptor, activating the IL-10/JAK1/STAT3 cascade to exert its effects. Therefore, STAT3 phosphorylation is essential for IL-10 actions. O-Glycosylation with linked β- N -acetylglucosamine (O-GlcNAc) is a post-translational modification able to regulate many proteins by interfering with protein on a phosphorylation level. Our aim was to determine whether O-GlcNAc promotes the inhibition of IL-10-pathway (JAK1/STAT3/IL-10), inactivationg its action in the vasculature. Main methods Mice (C57BL/6) aortic segments were incubated with vehicle or Thiamet G (0.1 mM, for 24 h) to increase global O -GlcNAc levels. Aortas from knockout mice for IL-10 were also used. Vascular reactivity and western blot tests were performed to evaluate protein expression. Key findings High levels of O -GlcNAc, induced by Thiamet G incubation, increased vascular expression of JAK1, but decreased expression and activity of STAT3. In addition, IL-10 levels were diminished in arteries treated with Thiamet G. Absence of IL-10, as well as augmented O-GlcNAcylation, increased vascular reactivity to constrictor stimuli, an effect that was abolished by ERK 1/2 inhibitor. High levels of O -GlcNAc and the absence of IL-10 also leads to increased vascular expression of ERK1/2. Significance Our data suggest that O-GlcNAc modification seems to (dys)regulate IL-10 signaling pathway and consequently, compromise the protective effect of this cytokine in vasculature. It is possible that there is a promising relationship in pathophysiological conditions where changes in O-GlcNAcylation and IL-10 levels are observed, such as hypertension and diabetes. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Objective: Population-based cohort studies suggest an association between osteoarthritis (OA) and cerebrovascular disease, yet the mechanisms underlying vascular comorbidities in OA remain unclear. The purpose of this narrative review is to discuss the literature examining inflammation in OA with a focus on physiological mechanisms, and whether overlapping mechanisms exist in cerebrovascular dysfunction.Method: A literature search was conducted in PubMed using combinations of search terms: osteoarthritis, cerebrovascular (disease/dysfunction/risk), cardiovascular (disease/dysfunction/risk), aging/ageing, inflammation, inflammatory mediators, cytokine, c-reactive protein, interleukin, advanced glycation end-products, metabolic syndrome, reactive oxidative species, cognitive impairment, (vascular-related) dementia, small cerebral vessel disease, endothelial function, blood-brain barrier, gender/sex, hypertension, peripheral vascular health, and physical activity. Reference lists of identified articles were also researched manually.Results: Overlapping inflammatory factors that may contribute to onset and progression of both OA and cerebrovascular dysfunction are presented. We describe oxidative mechanisms involving pro-inflammatory cytokines and oxidative species, advanced glycation end-products, sex hormones, microvascular dysfunction and osteoprotegerin, and their specific roles in potentially contributing to OA and cerebrovascular dysfunction.Conclusion: Synthesis of the current literature suggests future investigations may benefit from directly testing cerebrovascular hemodynamics and cognitive function in individuals with or at risk of OA to elucidate common physiological mechanisms. [ABSTRACT FROM AUTHOR]

Cardiovascular dysfunction and organ damage are hallmarks of sepsis and septic shock. Protein S -nitrosylation by nitric oxide has been described as an important modifier of protein function. We studied whether protein nitrosylation/denitrosylation would impact positively in hemodynamic parameters of septic rats. Polymicrobial sepsis was induced by cecal ligation and puncture. Female Wistar rats were treated with increasing doses of DTNB [5,5′-dithio-bis-(2-nitrobenzoic acid)] 30 min before or 4 or 12 h after sepsis induction. Twenty-four hours after surgery the following data was obtained: aorta response to phenylephrine, mean arterial pressure, vascular reactivity to phenylephrine, biochemical markers of organ damage, survival and aorta protein nitrosylation profile. Sepsis substantially decreases blood pressure and the response of aorta rings and of blood pressure to phenylephrine, as well as increased plasma levels of organ damage markers, mortality of 60% and S -nitrosylation of aorta proteins increased during sepsis. Treatment with DTNB 12 h after septic shock induction reversed the loss of response of aorta rings and blood pressure to vasoconstrictors, reduced organ damage and protein nitrosylation and increased survival to 80%. Increases in protein S -nitrosylation are related to cardiovascular dysfunction and multiple organ injury during sepsis. Treatment of rats with DTNB reduced the excessive protein S -nitrosylation, including that in calcium-dependent potassium channels (BK Ca ), reversed the cardiovascular dysfunction, improved markers of organ dysfunction and glycemic profile and substantially reduced mortality. Since all these beneficial consequences were attained even if DTNB was administered after septic shock onset, protein (de)nitrosylation may be a suitable target for sepsis treatment. [ABSTRACT FROM AUTHOR]

Pregnancy-associated vascular remodelling is essential for both maternal and fetal health. We have previously shown that maternal endothelial cell tetrahydrobiopterin (BH4) deficiency causes poor pregnancy outcomes. Here, we investigated the role and mechanisms of endothelial cell-mediated vasorelaxation function in these outcomes. The vascular reactivity of mouse aortas and uterine arteries from non-pregnant and pregnant endothelial cell-specific BH4 deficient mice (Gch1 fl/fl Tie2cre mice) was assessed by wire myography. Systolic blood pressure was assessed by tail cuff plethysmography. In late pregnancy, systolic blood pressure was significantly higher (∼24 mmHg) in Gch1 fl/fl Tie2cre mice compared with wild-type littermates. This was accompanied by enhanced vasoconstriction and reduced endothelial-dependent vasodilation in both aorta and uterine arteries from pregnant Gch1 fl/fl Tie2cre mice. In uterine arteries loss of eNOS-derived vasodilators was partially compensated by upregulation of intermediate and large-conductance Ca2+-activated K+ channels. In rescue experiments, oral BH4 supplementation alone did not rescue vascular dysfunction and pregnancy-induced hypertension in Gch1 fl/fl Tie2cre mice. However, combination with the fully reduced folate, 5-methyltetrahydrofolate (5-MTHF), restored endothelial cell vasodilator function and blood pressure. We identify a critical requirement for maternal endothelial cell Gch1 /BH4 biosynthesis in endothelial cell vasodilator function in pregnancy. Targeting vascular Gch1 and BH4 biosynthesis with reduced folates may provide a novel therapeutic target for the prevention and treatment of pregnancy-related hypertension. [Display omitted] [ABSTRACT FROM AUTHOR]

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H 2 S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H 2 S donor) and DL-Propargylglycine [DL-PAG; cystathionine-ץ-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1−7) [Ang-(1−7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1−7) and Ang II, and the expression of angiotensin AT 1 , AT 2 , and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT 1 receptor; 2) impaired Ang-(1−7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT 2 and angiotensin-(1−7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation. H 2 S improves vascular responses to Ang-(1−7) and Ang II impaired by HG. H 2 S restores Ang-(1−7) and Ang II serum levels during HG. H 2 S reestablishes ACE2 and angiotensin-(1−7) Mas receptor expression. H 2 S avoids changes in angiotensin II AT 1 and AT 2 receptors expression. [ABSTRACT FROM AUTHOR]

• Since the eye and brain form a unified hemodynamic continuum, the ocular circulation may be affected in the cerebral hemodynamic disorder described in epileptic patients. • Our aim was to evaluate whether decreased ocular perfusion accompanied the decreased cerebral blood flow independently of antiepileptic drug use. • Reduced ocular blood flow including choroidal vascular perfusion was observed in newly diagnosed epileptic children without any medication use. Decreased ocular perfusion may have an effect on the disturbance of visual function or the neurodegenerative process. To investigate the vascular changes of the optic nerve head (ONH) and macula by using optical coherence tomography angiography (OCT-A), and also the choroidal vascular structure by using an image binarization tool in children with newly diagnosed epilepsy and to then compare these parameters with healthy subjects. Forty-one epilepsy children and 36 healthy controls were included in this prospective and cross-sectional study. The radial peripapillary capillary (RPC) vessel density (VD) and macular foveal,parafoveal,perifoveal of superficial capillary plexus (SCP),deep capillary plexus (DCP) and choriocapillaris (CC) VD, and CC flow area were analyzed.Enhanced depth imaging (EDI) OCT scans of the macula were obtained and the images were binarized using the ImageJ software (National Institutes of Health, Bethesda, MD, USA).The subfoveal choroidal thickness (SFCT),the area of choroidal, luminal, and interstitial and the percentage of luminal area in the choroid (Choroidal vascular index (CVI)) were analyzed.We also evaluated the thickness of the peripapillary retinal nerve fiber layer (RNFL),the macular ganglion cell layer (GCL), and the inner plexiform layer (IPL). There was a significant decrease in the VD of the CC and the CC flow area in children with epilepsy compared to healthy subjects (p <0.05).However, the VD of the RPC, and of the SCP and DCP of the macula were similar between the two groups(p >0.05).The SFCT,choroidal area,luminal area, and CVI were statistically significant lower in children with newly diagnosed epilepsy compared to healthy subjects. This study has demonstrated that the choroidal perfusion from the microcirculation is lower in children with newly diagnosed epilepsy.The pathophysiology of epilepsy and neurodegenerative processes may also include this vascular dysfunction as one of the factors. [ABSTRACT FROM AUTHOR]

Nitroglycerin (Gtn) is a treatment for cardiovascular patients due to its vasodilatory actions, but induces tolerance when given chronically. A proposed mechanism is the superoxide (O 2 - )-oxidative stress hypothesis, which suggests that Gtn increases O 2 - production. Nitric oxide (NO) exists in three different redox states; the protonated, reduced state, nitroxyl anion (HNO) is an emerging candidate in vascular regulation. HNO is resistant to scavenging and of particular interest in conditions where high levels of reactive oxygen species (ROS) exist. We hypothesize that treatment with Gtn will exacerbate endothelin 1 (ET-1) induced vascular dysfunction via an increase in ROS, while treatment with Angeli's Salt (AS), an HNO donor, will not. Aorta from mice were isolated and divided into four groups: vehicle, ET-1 [0.1 μM, 1 μM], ET-1+Gtn [Gtn 1 μM] and ET-1+AS [AS 1 μM]. Concentration response curves (CRCs) to acetylcholine (ACh) and phenylephrine (Phe) were performed. Aorta incubated with ET-1 (for 20–22 h) exhibited a decreased relaxation response to ACh and an increase in Phe-mediated contraction. Aorta incubated with AS exhibited a reversal in ET-1 induced vascular and endothelial dysfunction. ET-1 increased ROS in aortic vascular smooth muscle cells (VSMCs), visualized by dihydroethidium (DHE) staining. AS incubated reduced this ROS generation, yet maintained with Gtn treatment. These data suggest that aorta incubated with the HNO donor, AS, can reverse ET-1 mediated vascular dysfunction, which may be through a decrease or prevention of ROS generation. We propose that HNO may be vasoprotective and that HNO donors studied as a therapeutic option where other organic nitrates are contraindicative. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the effects of egg white hydrolysate (EWH) on vascular disorders induced by mercury (Hg). For this, male Wistar rats were treated for 60 days: Untreated (saline, i.m .); Mercury (HgCl 2 , i.m ., 1st dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/day); Hydrolysate (EWH, gavage, 1 g/kg/day); Hydrolysate-Mercury. Systolic (SBP) and diastolic (DBP) blood pressure measurement and vascular reactivity experiments in aorta were performed. We analyzed endothelial dependent and independent vasodilator responses and vasoconstrictor response to phenylephrine (Phe) in absence and presence of endothelium, a NOS inhibitor, a NADPH oxidase inhibitor, the superoxide dismutase, a non-selective COX inhibitor, a selective COX-2 inhibitor, an AT-1 receptors blocker. In situ superoxide anion production, SOD-1, NOX-4, p22phox, COX-2 and AT-1 mRNA levels and NOX-1 protein expression were performed in aorta while the determination of angiotensin converting enzyme (ACE) activity was measured in plasma. As results, EWH prevented the increase in SBP and Phe responses and the endothelial dysfunction elicited by Hg, which was related to decreased ACE activity and NOX activation by EWH and, subsequently, alleviated ROS production and improved NO bioavailability in aorta. In conclusion, EWH could be considered as alternative or complementary treatment tools for Hg-induced cardiovascular damage. [ABSTRACT FROM AUTHOR]

Vascular dysfunction leading to hypotension is a major complication in patients with septic shock. Inducible nitric oxide synthase (iNOS) together with oxidative stress play an important role in development of vascular dysfunction in sepsis. Searching for an endogenous, safe and yet effective remedy was the chief goal for this study. The current study investigated the effect of agmatine (AGM), an endogenous metabolite of l -arginine, on sepsis-induced vascular dysfunction induced by lipopolysaccharides (LPS) in rats. AGM pretreatment (10 mg/kg, i.v.) 1 h before LPS (5 mg/kg, i.v.) prevented the LPS-induced mortality and elevations in serum creatine kinase-MB isoenzyme (CK-MB) activity, lactate dehydrogenase (LDH) activity, C-reactive protein (CRP) level and total nitrite/nitrate (NOx) level after 24 h from LPS injection. The elevation in aortic lipid peroxidation illustrated by increased malondialdehyde (MDA) content and the decrease in aortic glutathione (GSH) and superoxide dismutase (SOD) were also ameliorated by AGM. Additionally, AGM prevented LPS-induced elevation in mRNA expression of iNOS, while endothelial NOS (eNOS) mRNA was not affected. Furthermore AGM prevented the impaired aortic contraction to KCl and phenylephrine (PE) and endothelium-dependent relaxation to acetylcholine (ACh) without affecting endothelium-independent relaxation to sodium nitroprusside (SNP). In conclusion : AGM may represent a potential endogenous therapeutic candidate for sepsis-induced vascular dysfunction through its inhibiting effect on iNOS expression and oxidative stress. [ABSTRACT FROM AUTHOR]

Iron overload leads to excessive free radical formation and induces cardiovascular dysfunction. Thus, our aim was to investigate the structural and endothelial modulation of vascular tone induced by chronic iron overload in mesenteric arteries. Rats were divided into two groups: the control (vehicle) group and the group treated with iron dextran for 28 days (100 mg/kg, 5 days a week). Chronic iron overload altered the following morpho-physiological parameters of third-order mesenteric resistance arteries: decreased lumen and external diameters; increased wall/lumen ratio and wall thickness; decreased distensibility and increased stiffness; and increased pulse wave velocity. Additionally, iron overload increased the vasoconstrictor response in mesenteric arterial rings in vitro but did not affect the relaxation induced by acetylcholine and sodium nitroprusside. It is suggested that iron overload reduces nitric oxide bioavailability by increasing free radicals, because L-NAME did not shift the concentration-response curve to phenylephrine, but L-NAME plus superoxide dismutase shifted the curve to the left. In vitro assays with DAF-2 and DHE indicated reduced NO production and increased superoxide anion (O 2 − ) generation in the iron-overloaded group. Furthermore, tiron, catalase, apocynin and losartan induced reduced reactivity only in iron-overloaded rats. Moreover, increased ACE activity was observed in the mesenteric resistance arteries of iron-overloaded rats accompanied by an increase in gp91phox, catalase, ERK1/2 and eNOS protein expression. In conclusion, these findings show that chronic iron overload induces structural and functional changes in resistance arteries, most likely due to a decrease in NO bioavailability resulting from an increase in O 2 − production by NADPH oxidase. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) considered as a fatal mediator in the diabetic atherosclerotic pathology. In this study, we evaluated the effects of chebulic acid (CA) on anti-oxidant activities and its glycoaldehyde-induced AGEs (glycol-AGEs)-mediates systemic vascular dysfunction in endothelium, monocytes, and smooth muscle cells (SMC) co-culture condition. CA exhibited strong at free radical scavenging activity by blocking intracellular ROS formation in endothelium. They also suppressed endothelial activation by blocking the monocytes adhesion to endothelium, and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 as well as enhancing anti-oxidant detoxification defensing mediators such as HO-1 and NQO1 expression, through ERK/Nrf2 signaling in HUVEC. Furthermore, CA administration provided powerful anti-inflammatory supplements to mice, and also has similar results by enhancing Nrf2, and their down-streamed mediators. These in vitro and in vivo studies indicated that CA attenuated glycol-AGEs-mediates vascular dysfunction by ameliorating AGEs-induced inflammation and oxidative stress via enhancing the detoxification defensing pathway of ERK/Nrf2. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR), a chronic and progressive complication of diabetes mellitus, is a sight-threatening disease characterized in the early stages by neuronal and vascular dysfunction in the retina, and later by neovascularization that further damages vision. A major contributor to the pathology is excess production of vascular endothelial growth factor (VEGF), a growth factor that induces formation of new blood vessels and increases permeability of existing vessels. Despite the recent availability of effective treatments for the disease, including laser photocoagulation and therapeutic VEGF antibodies, DR remains a significant cause of vision loss worldwide. Existing anti-VEGF agents, though generally effective, are limited by their short therapeutic half-lives, necessitating frequent intravitreal injections and the risk of attendant adverse events. Management of DR with gene therapies has been proposed for several years, and pre-clinical studies have yielded enticing findings. Gene therapy holds several advantages over conventional treatments for DR, such as a longer duration of therapeutic effect, simpler administration, the ability to intervene at an earlier stage of the disease, and potentially fewer side-effects. In this review, we summarize the current understanding of the pathophysiology of DR and provide an overview of research into DR gene therapies. We also examine current barriers to the clinical application of gene therapy for DR and evaluate future prospects for this approach. [ABSTRACT FROM AUTHOR]

Nandrolone Decanoate (ND) is an Anabolic Androgenic Steroid (AAS) that under abusive regimen can lead to multiple physiological adverse effects. Studies of AAS-mediated cardiovascular (CV) alterations were mostly taken from male subjects, even though women are also susceptible to the effects of AAS and gender-specific differences in susceptibility to vascular diseases exist. Here we investigate ND-induced vascular reactivity alterations in both sedentary and exercised female rats and whether these alterations depend on endothelium-derived factors. We show that chronic exposure of female Wistar rats to ND (20 mg/Kg/week for 4 weeks) impaired the vascular mesenteric bed (MVB) reactivity to vasodilator (acetylcholine) agonist. The endothelium-dependent Nitric Oxide (NO) component was reduced in ND-treated rats, whereas neither the endothelium-derived hyperpolarizing factor (EDHF) component nor prostanoids were altered in the MVBs. Endothelial dysfunction observed in ND-treated rats was associated with decreased eNOS (Ser 1177 ) and Akt (Ser 473 ) phosphorylation sites and upregulation of iNOS and NADPH oxidase expression. Exercise training by weight lifting in water did not improve the vascular alterations induced by ND treatment. ND treatment also significantly reduced the serum levels of estradiol in females, overriding its CV protective effect. These results help uncover the role of ND modulating endothelial function in the setting of CV disease caused by the abuse of AAS in females. If this translates to humans, young women abusing AAS can potentially lose the cardio protective effect rendered by estrogen and be more susceptible to CV alterations. [ABSTRACT FROM AUTHOR]

Background and aims Modern tobacco regulatory science requires an understanding of which biomarkers of cardiovascular injury are most sensitive to cigarette smoking exposure. Methods We studied self-reported current smokers from the Multi-Ethnic Study of Atherosclerosis. Smoking intensity was defined by number of cigarettes/day and urinary cotinine levels. Subclinical cardiovascular injury was assessed using markers of inflammation [high-sensitivity C-reactive protein (hsCRP), interleukin 6 & 2 (IL-2 & IL-6), tumor necrosis factor alpha (TNF-α)], thrombosis (fibrinogen, D-dimer, homocysteine), myocardial injury (troponin T; TnT), endothelial damage (albumin: creatinine ratio), and vascular function [aortic & carotid distensibility, flow-mediated dilation (FMD)]. Biomarkers were modeled as absolute and percent change using multivariable-adjusted linear regression models adjusted for cardiovascular risk factors and smoking duration. Results Among 843 current smokers, mean age was 58 (9) years, 53% were men, 39% were African American, mean number of cigarettes per day was 13 (10), and median smoking duration was 39 (15) years. Cigarette count was significantly associated with higher hsCRP, IL-6 and fibrinogen (β coefficients: 0.013, 0.011, 0.60 respectively), while ln-transformed cotinine was associated with the same biomarkers (β coefficients: 0.12, 0.04, 5.3 respectively) and inversely associated with aortic distensibility (β coefficient: −0.13). There was a limited association between smoking intensity and homocysteine, D-dimer, and albumin:creatinine ratio in partially adjusted models only, while there was no association with IL-2, TNF-α, carotid distensibility, FMD, or TnT in any model. In percent change analyses, relationships were strongest with hsCRP. Conclusions Smoking intensity was associated with early biomarkers of CVD, particularly, markers of systemic inflammation. Of these, hsCRP may be the most sensitive. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a chronic and progressive disease, is a leading cause of endothelial dysfunction, diabetes mellitus, hypertension, and hypercholesterolemia. Betulinic acid (BA), a pentacyclic triterpene, has been reported to have a variety of biological effects, including anti-inflammatory and immunomodulatory properties. This study was designed to determine whether BA could prevent atherosclerosis in diabetic apolipoprotein-E gene knockout (ApoE KO) mice. The mice were treated with BA for 12 weeks to examine its beneficial effects on atherosclerosis in ApoE KO mice. Male ApoE KO mice and age-matched control group mice (C57BL/6Jms) were used as experimental systems and their systolic blood pressure, insulin resistance, and vascular inflammation were measured. BA-treated ApoE KO mice showed lowered systolic blood pressure. The metabolic parameter showed that BA decreased blood urea nitrogen, triglyceride, and total cholesterol levels. Blood glucose, insulin, glucose tolerance results, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were found to be better in BA-treated ApoE KO mice than untreated ApoE KO mice. Consistent with the change in lipid profiles, oil red O and H&E staining revealed that treatment with BA reduced atherosclerotic lesions such as roughened endothelial layers. BA ameliorated the reduction of endothelial nitric oxide synthase (eNOS) expression, leading to the inhibition of intracellular adhesion molecule 1 (ICAM-1) and endothelin 1 (ET-1) expression. These results suggest that BA may be useful in the treatment and prevention of early atherosclerosis via the attenuation of endothelial dysfunction in diabetic ApoE KO mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • EWH pretreatment prevents the SBP increase and vascular dysfunction caused by Cd. • EWH pretreatment prevented the increase of oxidative stress caused by Cd in MRA. • EWH pretreatment prevents the increase of pro-inflammatory markers induced by Cd. • EWH pretreatment protects MRA from Caspase-3 activation, an apoptotic protease. We investigated whether pretreatment with an egg white hydrolysate (EWH) protects the cardiovascular system, especially the resistance vessels, from damage promoted by Cd exposure at high levels. Male Wistar rats, divided into groups: 1) Control – tap water by gavage + distilled water i.p. (28 days); 2) Cd – tap water (28 days) + CdCl 2 1 mg/kg i.p. (last 14 days); 3) EWH 1 mg/kg/day by gavage + distilled water i.p. (28 days); 4) EWHCd – EWH (first 14 days) and CdCl 2 i.p. + EWH (last 14 days). EWH pretreatment protected against vascular damage occurring in mesenteric resistance arteries (MRA) after exposure to elevated Cd levels by reducing the increased vascular contractile response. Pretreatment with EWH maintained SBP at control levels, protected against increased oxidative stress through NOX1 pathway, prevented triggering of inflammatory cascades (COX-2, TNFα, NF-κB), and protected MRA from Caspase-3 activation induced by Cd, an important apoptotic protease. [ABSTRACT FROM AUTHOR]

Excessive iron can generate reactive oxygen species (ROS), leading to oxidative stress that is closely associated with cardiovascular dysfunction. Iron overload was induced in male ICR mice by injection of iron sucrose (10 mg/kg/day) for eight weeks. Iron overload was evidenced by increased serum iron indices. The mice developed increased blood pressure, impaired vascular function and blunted response of the autonomic nervous system. These effects were accompanied by increased malondialdehyde levels in various tissues, increased nitric oxide metabolites in plasma and urine, and decreased blood glutathione. Tetrahydrocurcumin (THU, 50 mg/kg/day), deferiprone (or L1, 50 mg/kg/day) or both was orally administered throughout the period of iron sucrose injection. The treatments significantly alleviated the deleterious cardiovascular effects of iron overload, and were associated with modulation of nitric oxide levels. An imbalance between endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in response to iron overload was normalized by THU, L1 or the combination treatment. Moreover, the treatment decreased the upregulated expression levels of gp91 phox , p47 phox and HO-1. The combination of THU and L1 exerted a greater effect than THU or L1 monotherapy. These results suggest beneficial effects of THU and L1 on iron-induced oxidative stress, hypertension, and vascular dysfunction. [ABSTRACT FROM AUTHOR]

Background and Aims: Increased arterial stiffness is closely linked with raised blood pressure that contributes substantially to enhanced risk of coronary heart disease in high risk individuals with familial hypercholesterolaemia (FH). Omega-3 fatty acid (ω3-FA) supplementation has been demonstrated to lower blood pressure in subjects with a high cardiovascular disease risk. Whether ω3-FA supplementation improves arterial stiffness in FH subjects, on background statin therapy, has yet to be investigated.Method and Results: We carried out an 8-week randomized, crossover intervention trial to test the effect of 4 g/d ω3-FA supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on arterial elasticity in 20 adults with FH on optimal cholesterol-lowering therapy. Large and small artery elasticity were measured by pulse contour analysis of the radial artery. ω3-FA supplementation significantly (P < 0.05 in all) increased large artery elasticity (+9%) and reduced systolic blood pressure (-6%) and diastolic blood pressure (-6%), plasma triglycerides (-20%), apoB concentration (-8%). In contrast, ω3-FAs had no significant effect on small artery elasticity. The change in large artery elasticity was not significantly associated with changes in systolic blood pressure or plasma triglyceride concentration.Conclusions: ω3-FA supplementation improves large arterial elasticity and arterial blood pressure independent of statin therapy in adults with FH.Clinical Trial Registration: https://www.clinicaltrials.com/NCT01577056. [ABSTRACT FROM AUTHOR]

To assess the effects of subchronic administration with NaHS, an exogenous H 2 S donor, on TBI-induced hypertension and vascular impairments. Animals underweministration does not prevent the body weight loss but slightly imnt a lateral fluid percussion injury, and the hemodynamic variables were measured in vivo by plethysmograph method. The vascular function in vitro, the ROS levels by the DCFH-DA method and the expression of H 2 S-synthesizing enzymes and eNOS by Western blot were measured in isolated thoracic aortas at day 7 post-TBI. The effect of L-NAME on NaHS-induced effects in vascular function was evaluated. Brain water content was determined 7 days after trauma induction. Body weight was recorded throughout the experimental protocol, whereas the sensorimotor function was evaluated using the neuroscore test at days −1 (basal), 2, and 7 after the TBI induction. TBI animals showed: 1) an increase in hemodynamic variables and ROS levels in aortas; 2) vascular dysfunction; 3) sensorimotor dysfunction; and 4) a decrease in body weight, the expression of H 2 S-synthesizing enzymes, and eNOS phosphorylation. Interestingly, NaHS subchronic administration (3.1 mg/kg; i.p.; every 24 h for six days) prevented the development of hypertension, vascular dysfunction, and oxidative stress. L-NAME abolished NaHS-induced effects. Furthermore, NaHS treatment restored H 2 S-synthesizing enzymes and eNOS phosphorylation with no effect on body weight, sensorimotor impairments, or brain water content. Taken together, these results demonstrate that H 2 S prevents TBI-induced hypertension by restoring vascular function and modulating ROS levels, H 2 S-synthesizing enzymes expression, and eNOS phosphorylation. [ABSTRACT FROM AUTHOR]

Vascular dysfunction is a clinical hallmark of diabetes. While various pathways drive vascular alterations in diabetes, many gaps persist in understanding this process. Heat-shock protein 70 (HSP70) has a long-recognized role in diabetes, but the contributions of HSP70 to the diabetic vasculature remain largely unknown. We determined the systemic and local (aorta) levels of HSP70 in control (CTL) and streptozotocin (STZ)-induced diabetic rats. Functional studies were conducted in a wire myograph in the presence or absence of a pharmacological inhibitor for HSP70 (VER155008). Calcium (Ca2+) dynamics was indirectly evaluated as a function of change in force development in vehicle and VER-treated vessels, as well as in the presence of inhibitors for voltage-dependent and -independent plasmalemmal Ca2+ channels. Furthermore, mimicking the extracellular diabetic environment, we exposed aortic rings to serum from CTL and STZ-induced animals, which contains higher levels of HSP70, as well as to purified recombinant HSP70. Then, we performed functional studies following the modulation of Toll-like receptor 4 (TLR4) and its co-adaptor MD2, which interact with HSP70. HSP70 plays a dual role in diabetes-induced vascular dysfunction: intracellular (i)HSP70 affects Ca2+ handling mechanisms, and extracellular (e)HSP70 modulates the TLR4-MD2 complex. These newly discovered roles of HSP70 push forward the field of vascular biology and open research avenues for other diseased states associated with altered vascular responses. [Display omitted] [ABSTRACT FROM AUTHOR]

Vascular disorders have a direct link to mortality in the acute phase of Trypanosoma cruzi infection. However, the underlying mechanisms of vascular dysfunction in this phase are largely unknown. We hypothesize that T. cruzi invades endothelial cells causing dysfunction in contractility and relaxation of the mouse aorta. Immunodetection of T. cruzi antigen TcRBP28 was observed in endothelial cells. There was a decreased endothelial nitric oxide synthase (eNOS)-derived NO-dependent vascular relaxation, and increased vascular contractility accompanied by augmented superoxide anions production. Endothelial removal, inhibition of cyclooxygenase 2 (COX-2), blockade of thromboxane A 2 (TXA 2 ) TP receptors, and scavenger of superoxide normalized the contractile response. COX-2, thromboxane synthase, inducible nitric oxide synthase (iNOS), p65 NFκB subunit and p22 phox of NAD(P)H oxidase (NOX) subunit expressions were increased in vessels of chagasic animals. Serum TNF-α was augmented. Basal NO production, and nitrotyrosine residue expression were increased. It is concluded that T. cruzi invades mice aorta endothelial cells and increases TXA 2 /TP receptor/NOX-derived superoxide formation. Alongside, T. cruzi promotes systemic TNF-α increase, which stimulates iNOS expression in vessels and nitrosative stress. In light of the heart failure that develops in the chronic phase of the disease, to understand the mechanism involved in the increased contractility of the aorta is crucial. [ABSTRACT FROM AUTHOR]

This work was designed to investigate the effects of levocetirizine, a histamine H 1 receptor antagonist, on diabetes-induced nephropathy and vascular disorder, in comparison to an angiotensin II receptor antagonist, losartan. Diabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of streptozotocin (50 mg/kg). Diabetic rats were divided into three groups; diabetic, diabetic-levocetirizine (0.5 mg/kg/day) and diabetic-losartan (25 mg/kg/day). Treatments were started two weeks following diabetes induction and continued for additional eight weeks. At the end of the experiment, urine was collected and serum was separated for biochemical measurements. Tissue homogenates of kidney and aorta were prepared for measuring oxidative stress, nitric oxide (NO), transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α). Moreover, histological analyses were conducted and aortic vascular reactivity was investigated. Levocetirizine improved renal function in diabetic rats (evidenced by mitigation of diabetes-induced changes in kidney to body weight ratio, serum albumin, urinary proteins and creatinine clearance). Moreover, levocetirizine attenuated the elevated renal levels of TNF-α and TGF-β1, ameliorated renal oxidative stress and restored NO bioavailability in diabetic kidney. These effects were comparable to or surpassed those produced by losartan. Moreover, levocetirizine, similar to losartan, reduced the enhanced responsiveness of diabetic aorta to phenylephrine. Histological evaluation of renal and aortic tissues further confirmed the beneficial effects of levocetirizine on diabetic nephropathy and revealed a greater attenuation of diabetes-induced vascular hypertrophy by levocetirizine than by losartan. In conclusion, levocetirizine may offer comparable renoprotective effect to, and possibly superior vasculoprotective effects than, losartan in streptozotocin-diabetic rats. [ABSTRACT FROM AUTHOR]