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Ablation of nucleoside diphosphate kinase B (NDPK-B) in mice causes a breakdown of the neurovascular unit in the retina, mimicking diabetic retinopathy. The NDPK-B deficiency-induced vascular damage is mediated by excessive angiopoietin 2 (Ang2). Herein, the potential involvement of its receptor, Tie2, was investigated. NDPK-B-deficient mouse retinas showed an upregulation of Tie2, specifically in the deep capillary layer. A similar upregulation of Tie2 was observed in cultured endothelial cells (ECs) from different origins upon NDPK-B depletion, whereas high glucose (HG) treatment did not alter Tie2 expression. Immunofluorescence staining and subcellular fractionation showed that the majority of Tie2 upregulation occurred at the plasma membrane. Similar to HG, however, NDPK-B depletion reduced Tie2 tyrosine phosphorylation. Compared to HG, a stronger increase of Ang2 was observed in NDPK-B depleted ECs. Treatment of ECs with soluble Tie2 or siRNA-mediated Tie2 knockdown attenuated NDPK-B depletion- but not HG-induced Ang2 upregulation. Like NDPK-B depletion, overexpression of recombinant Ang2 in ECs enhanced Ang2 secretion and concomitantly promoted the upregulation of Tie2. Thus, we identified a new mechanism showing that after reaching a threshold level of secretion, Ang2 sustains its own expression and secretion by a Tie2-dependent positive feedback loop.

Although initial immunophenotypical studies on peripheral blood and bronchoalveolar lavage samples have provided a glimpse into the immunopathology of COVID-19, analyses of pulmonary draining lymph nodes are currently scarce. 22 lethal COVID-19 cases and 28 controls were enrolled in this study. Pulmonary draining lymph nodes (mediastinal, tracheal, peribronchial) were collected at autopsy. Control lymph nodes were selected from a range of histomorphological sequelae [unremarkable histology, infectious mononucleosis, follicular hyperplasia, non-SARS related HLH, extrafollicular plasmablast activation, non-SARS related diffuse alveolar damage (DAD), pneumonia]. Samples were mounted on a tissue microarray and underwent immunohistochemical staining for a selection of immunological markers and in-situ hybridization for Epstein Barr Virus (EBV) and SARS-CoV-2. Gene expression profiling was performed using the HTG EdgeSeq Immune Response Panel. Characteristic patterns of a dysregulated immune response were detected in COVID-19: 1. An accumulation of extrafollicular plasmablasts with a relative paucity or depletion of germinal centers. 2. Evidence of T-cell dysregulation demonstrated by immunohistochemical paucity of FOXP3+, Tbet+ and LEF1+ positive T-cells and a downregulation of key genes responsible for T-cell crosstalk, maturation and migration as well as a reactivation of herpes viruses in 6 COVID-19 lymph nodes (EBV, HSV). 3. Macrophage activation by a M2-polarized, CD163+ phenotype and increased incidence of hemophagocytic activity. 4. Microvascular dysfunction, evidenced by an upregulation of hemostatic (CD36, PROCR, VWF) and proangiogenic (FLT1, TEK) genes and an increase of fibrin microthrombi and CD105+ microvessels. Taken together, these findings imply widespread dysregulation of both innate and adoptive pathways with concordant microvascular dysfunction in severe COVID-19.

Alzheimer’s disease is the most common form of dementia, and epidemiological studies support that type 2 diabetes (T2D) is a major contributor. The relationship between both diseases and the fact that Alzheimer’s disease (AD) does not have a successful treatment support the study on antidiabetic drugs limiting or slowing down brain complications in AD. Among these, liraglutide (LRGT), a glucagon-like peptide-1 agonist, is currently being tested in patients with AD in the Evaluating Liraglutide in Alzheimer’s Disease (ELAD) clinical trial. However, the effects of LRGT on brain pathology when AD and T2D coexist have not been assessed. We have administered LRGT (500 μg/kg/day) to a mixed murine model of AD and T2D (APP/PS1xdb/db mice) for 20 weeks. We have evaluated metabolic parameters as well as the effects of LRGT on learning and memory. Postmortem analysis included assessment of brain amyloid-β and tau pathologies, microglia activation, spontaneous bleeding and neuronal loss, as well as insulin and insulin-like growth factor 1 receptors. LRGT treatment reduced glucose levels in diabetic mice (db/db and APP/PS1xdb/db) after 4 weeks of treatment. LRGT also helped to maintain insulin levels after 8 weeks of treatment. While we did not detect any effects on cortical insulin or insulin-like growth factor 1 receptor m-RNA levels, LRGT significantly reduced brain atrophy in the db/db and APP/PS1xdb/db mice. LRGT treatment also rescued neuron density in the APP/PS1xdb/db mice in the proximity (p = 0.008) far from amyloid plaques (p < 0.001). LRGT reduced amyloid plaque burden in the APP/PS1 animals (p < 0.001), as well as Aβ aggregates levels (p = 0.046), and tau hyperphosphorylation (p = 0.009) in the APP/PS1xdb/db mice. Spontaneous bleeding was also ameliorated in the APP/PS1xdb/db animals (p = 0.012), and microglia burden was reduced in the proximity of amyloid plaques in the APP/PS1 and APP/PS1xdb/db mice (p < 0.001), while microglia was reduced in areas far from amyloid plaques in the db/db and APP/PS1xdb/db mice (p < 0.001). This overall improvement helped to rescue cognitive impairment in AD-T2D mice in the new object discrimination test (p < 0.001) and Morris water maze (p < 0.001). Altogether, our data support the role of LRGT in reduction of associated brain complications when T2D and AD occur simultaneously, as regularly observed in the clinical arena.

In epilepsy, the most frequent surgical procedure is the resection of brain tissue in the temporal lobe, with seizure-free outcomes in approximately two-thirds of cases. However, consequences of surgery can vary strongly depending on the brain region targeted for removal, as surgical morbidity and collateral damage can lead to significant complications, particularly when bleeding and swelling are located near delicate functional cortical regions. Although focal thermal ablations are well-explored in epilepsy as a minimally invasive approach, hemorrhage and edema can be a consequence as the blood-brain barrier is still disrupted. Non-thermal irreversible electroporation (NTIRE), common in many other medical tissue ablations outside the brain, is a relatively unexplored method for the ablation of neural tissue, and has never been reported as a means for ablation of brain tissue in the context of epilepsy. Here, we present a detailed visualization of non-thermal ablation of neural tissue in mice and report that NTIRE successfully ablates epileptic foci in mice, resulting in seizure-freedom, while causing significantly less hemorrhage and edema compared to conventional thermal ablation. The NTIRE approach to ablation preserves the blood-brain barrier while pathological circuits in the same region are destroyed. Additionally, we see the reinnervation of fibers into ablated brain regions from neighboring areas as early as day 3 after ablation. Our evidence demonstrates that NTIRE could be utilized as a precise tool for the ablation of surgically challenging epileptogenic zones in patients where the risk of complications and hemorrhage is high, allowing not only reduced tissue damage but potentially accelerated recovery as vessels and extracellular matrix remain intact at the point of ablation.

Hazardous impacts of subacute exposure to atmospheric particulate matter (PM) on the vascular system are not fully understood. Much emphasis has been put on apparent pathological alterations previously, but early checkpoints were scarcely centralized in the course of cardiovascular disequilibria, such as the cellular or/and subcellular visions. In the current study, a tertiary assessment was implemented, including aortic tissues, vascular cells and subcellular equilibrium. As a result, subacute PM aspiration exerted negligible effects on lipids deposition of vascular walls. However, adverse effects were determined at the cellular and subcellular levels, such as endothelial monolayer disintegration and organelle dysfunction. Specifically, endoplasmic reticulum (ER) stress and mitochondrial malfunction were provoked by PM stimulus. Furthermore, correlation analysis suggested a strong association between aortic ox-inflammatory cascade and vascular subcellular disequilibrium. Altogether, subcellular, cellular and histological levels were assessed to gain a comprehensive understanding of vascular toxicity by realistic concentrations of PM, from which even in the absence of pathological changes, vascular endothelial cells and subcellular structures were predominantly damaged. In particulate toxicology, the necessity of early checkpoints needs to be further strengthened.

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex. NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.

Introduction: The vascular cell adhesion molecule (VCAM-1) is a transmembrane sialoglycoprotein detected in activated endothelial and vascular smooth muscle cells involved in the adhesion and transmigration of inflammatory cells into damaged tissue. Widely used as a pro-inflammatory marker, its potential role as a targeting molecule has not been thoroughly explored., Areas Covered: We discuss the current evidence supporting the potential targeting of VCAM-1 in atherosclerosis, diabetes, hypertension and ischemia/reperfusion injury., Expert Opinion: There is emerging evidence that VCAM-1 is more than a biomarker and may be a promising therapeutic target for vascular diseases. While there are neutralizing antibodies that allow preclinical research, the development of pharmacological tools to activate or inhibit this protein are required to thoroughly assess its therapeutic potential.

Norihiro Sakai,1,* Kenya Kamimura,1,* Yoko Shinagawa-Kobayashi,1 Takuro Nagoya,1 Yusuke Niwa,1 Masayoshi Ko,1 Toru Setsu,1 Akira Sakamaki,1 Takeshi Yokoo,1 Satoshi Abe,1 Hiroteru Kamimura,1 Soichi Sugitani,2 Masahiko Yanagi,3 Shuji Terai11Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; 2Department of Gastroenterology, Murakami General Hospital, Murakami, Niigata, Japan; 3Department of Gastroenterology, Ojiya General Hospital, Ojiya, Niigata, Japan*These authors contributed equally to this workBackground: Sorafenib (SOR) is an anti-angiogenic chemotherapeutic that prolongs the survival rates of patients with hepatocellular carcinoma. However, SOR also damages normal vasculature and causes associated adverse events, including hand–foot syndrome and hypertension (HT). We previously reported in an animal study that vascular damage resulted in the narrowing of the normal vascular dimension area in medaka fish (Oryzias), and histidine (HIS), a major amino acid contained in dried bonito broth (DBB), prevented these changes. Therefore, in the study, we analyzed the effects of DBB and HIS on SOR-related vascular damages and associated adverse events in patients.Materials and methods: Three-dimensional (3D) vascular images of abdominal regions reconstituted from computed tomography were assessed to compare vascular diameter prior to and following SOR administration in groups receiving SOR monotherapy, DBB+SOR, and HIS+SOR. The clinical courses of hand–foot syndrome and HT and the toxicities of SOR in biochemical assays were monitored and compared between the groups. Correlations between hepatic function and SOR-related changes in the portal venous area dimension were also assessed.Results: SOR-related vascular damage revealed narrowing of the normal abdominal vasculature in the human body, which was monitored using 3D images. The damage was ameliorated by DBB and HIS, however, HIS had a more marked effect, particularly on the renal arteries and portal vein (PV). Maintenance of blood flow contributed to the maintenance of total cholesterol, prothrombin time, albumin (ALB), and renal functions. Changes in the 3D vascular area dimension of the PV and level of serum ALB were significantly correlated. The occurrences of the clinical symptoms of hand–foot syndrome and HT were lower in the DBB- and HIS-treated groups.Conclusion: Our results clearly demonstrate that DBB and HIS prevented SOR-related abdominal vascular damage and effectively maintained hepatic function, and prevented clinical symptoms and toxicity.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000025937 and UMIN000026898).Keywords: sorafenib, histidine, dried bonito broth, vascular area dimension, albumin, hepatocellular carcinoma

Diabetes mellitus (DM) is a rapidly increasing problem in health care worldwide: recent forecast indicates that the number of DM patients will rise to 640 million by 2040. Vascular damage is associated with severe complications, including cardiac neuropathy and limb amputation. Therefore, early prediction of diabetic vascular damage using advanced technologies is an important challenge because timely preventive and therapeutic measures could diminish the risk of development and burden of complications. The aim of the article is to provide a review of the initial stages of vascular damage and main mechanisms for development, as well as appropriate modern technologies for prediction and diagnosis. The manuscript provides an overview of interrelated vascular damage mechanisms influenced by diabetes, along with a review of possible technologies for early prediction and diagnosis. A comparative analysis of technologies appropriate for particular issues of prediction is summarised in the discussion.

Objectives. To study the clinical and immunological features of cardiac and vascular damage in children with juvenile arthritis with systemic onset. Materials and methods. The study included 30 children with juvenile arthritis with systemic onset who were hospitalized in the cardio-rheumatology department of the Republican Specialized Scientific and Practical Medical Center of Pediatrics. All patients underwent clinical and anamnestic, functional, instrumental and laboratory research methods. Conclusion. Clinical and immunological features of lesions of the heart and blood vessels in children with JAWSO depend on the timing of the disease manifestation, the activity of the systemic inflammatory process and are characterized by impaired functional activity of the heart, overexpression of vascular endothelial growth factor VEGF, which determines the degree of risk of cardiovascular complications in this pathology. [ABSTRACT FROM AUTHOR]

Abstract Background Neuroinflammation often develops in sepsis leading to activation of cerebral endothelium, increased permeability of the blood-brain barrier (BBB), and neutrophil infiltration. We have identified protein kinase C-delta (PKCδ) as a critical regulator of the inflammatory response and demonstrated that pharmacologic inhibition of PKCδ by a peptide inhibitor (PKCδ-i) protected endothelial cells, decreased sepsis-mediated neutrophil influx into the lung, and prevented tissue damage. The objective of this study was to elucidate the regulation and relative contribution of PKCδ in the control of individual steps in neuroinflammation during sepsis. Methods The role of PKCδ in mediating human brain microvascular endothelial (HBMVEC) permeability, junctional protein expression, and leukocyte adhesion and migration was investigated in vitro using our novel BBB on-a-chip (B3C) microfluidic assay and in vivo in a rat model of sepsis induced by cecal ligation and puncture (CLP). HBMVEC were cultured under flow in the vascular channels of B3C. Confocal imaging and staining were used to confirm tight junction and lumen formation. Confluent HBMVEC were pretreated with TNF-α (10 U/ml) for 4 h in the absence or presence of PKCδ-i (5 μM) to quantify neutrophil adhesion and migration in the B3C. Permeability was measured using a 40-kDa fluorescent dextran in vitro and Evans blue dye in vivo. Results During sepsis, PKCδ is activated in the rat brain resulting in membrane translocation, a step that is attenuated by treatment with PKCδ-i. Similarly, TNF-α-mediated activation of PKCδ and its translocation in HBMVEC are attenuated by PKCδ-i in vitro. PKCδ inhibition significantly reduced TNF-α-mediated hyperpermeability and TEER decrease in vitro in activated HBMVEC and rat brain in vivo 24 h after CLP induced sepsis. TNF-α-treated HBMVEC showed interrupted tight junction expression, whereas continuous expression of tight junction protein was observed in non-treated or PKCδ-i-treated cells. PKCδ inhibition also reduced TNF-α-mediated neutrophil adhesion and migration across HBMVEC in B3C. Interestingly, while PKCδ inhibition decreased the number of adherent neutrophils to baseline (no-treatment group), it significantly reduced the number of migrated neutrophils below the baseline, suggesting a critical role of PKCδ in regulating neutrophil transmigration. Conclusions The BBB on-a-chip (B3C) in vitro assay is suitable for the study of BBB function as well as screening of novel therapeutics in real-time. PKCδ activation is a key signaling event that alters the structural and functional integrity of BBB leading to vascular damage and inflammation-induced tissue damage. PKCδ-TAT peptide inhibitor has therapeutic potential for the prevention or reduction of cerebrovascular injury in sepsis-induced vascular damage.

The projected responses of forest ecosystems to warming and drying associated with twenty-first-century climate change vary widely from resiliency to widespread tree mortality. Current vegetation models lack the ability to account for mortality of overstorey trees during extreme drought owing to uncertainties in mechanisms and thresholds causing mortality. Here we assess the causes of tree mortality, using field measurements of branch hydraulic conductivity during ongoing mortality in Populus tremuloides in the southwestern United States and a detailed plant hydraulics model. We identify a lethal plant water stress threshold that corresponds with a loss of vascular transport capacity from air entry into the xylem. We then use this hydraulic-based threshold to simulate forest dieback during historical drought, and compare predictions against three independent mortality data sets. The hydraulic threshold predicted with 75% accuracy regional patterns of tree mortality as found in field plots and mortality maps derived from Landsat imagery. In a high-emissions scenario, climate models project that drought stress will exceed the observed mortality threshold in the southwestern United States by the 2050s. Our approach provides a powerful and tractable way of incorporating tree mortality into vegetation models to resolve uncertainty over the fate of forest ecosystems in a changing climate.

Background: Cigarette smoking promotes vascular endothelial damage and accelerates progression of atherosclerosis. The purpose of this study was to examine whether the circulating level of vascular endothelium-enriched microRNA-126 (miR-126), which is highlighted as a regulator of gene expression, would serve as a novel biomarker for recovery from smoking-related vascular damage. Methods: Middle-aged male smokers (n = 30) were enrolled and instructed to stop smoking. Their clinical profiles and laboratory findings including expression of miR-126 were investigated before and after 8 weeks of smoking cessation. Serum levels of cotinine, metabolites of nicotine, were measured to confirm smoking cessation. Endothelial function for peripheral small vessels was assessed and expressed as reactive hyperemia peripheral arterial tonometry (RH-PAT) index. The expression of miR-126 in plasma was analyzed by quantitative real-time PCR. Results: At baseline, serum cotinine levels were inversely correlated with RH-PAT index (r = −0.48, P

Vitamin D3 deficiency, obesity, and diabetes mellitus (DM) have been shown to increase the risk of cardiovascular diseases (CVDs). However, the early detection of vascular damage in those patients is still difficult to ascertain. MicroRNAs (miRNAs) are recognized to play a critical role in initiation and pathogenesis of vascular dysfunction. Herein, we aimed to identify circulating miRNA biomarkers of vascular dysfunction as early predictors of CVDs. We have recruited 23 middle-aged Emiratis patients with the following criteria: A healthy control group with vitamin D ≥ 20ng, and BMI < 30 (C1 group = 11 individuals); A vitamin D deficiency (Vit D level ≤ 20 ng) and obese (BMI ≥ 30) group (A1 group = 9 patients); A vitamin D deficiency, obese, plus DM (A2 group = 3 patients). Arterial stiffness via pulse wave velocity (PWV) was measured and the whole transcriptome analysis with qPCR validation for miRNA in plasma samples were tested. PWV relative to age was significantly higher in A1 group 19.4 ± 4.7 m/s and A2 group 18.3 ± 1.3 m/s compared to controls 14.7 ± 2.1 m/s (p < 0.05). Similar patterns were also observed in the Augmentation pressure (AP) and Alx%. Whole RNA-Sequencing revealed miR-182-5p; miR-199a-5p; miR-193a-5p; and miR-155-5p were differentially over-expressed (logFC > 1.5) in high-risk patients for CVDs vs healthy controls. Collectively, our result indicates that four specific circulating miRNA signature, may be utilized as non-invasive, diagnostic and prognostic biomarkers for early vascular damage in patients suffering from vitamin D deficiency, obesity and DM. [ABSTRACT FROM AUTHOR]

The development of type 2 diabetes mellitus (T2DM) vascular complications (VCs) is associated with oxidative stress and chronic inflammation and can result in endothelial dysfunctions. Circulating microRNAs play an important role in epigenetic regulation of the etiology of T2DM. We studied 30 healthy volunteers, 26 T2DM patients with no complications, and 26 T2DM patients with VCs, to look for new biomarkers indicating a risk of developing VCs in T2DM patients. Peripheral blood samples were used to determine redox state, by measuring the endogenous antioxidant defense system (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione peroxidase, GPx; and glucose-6-phosphate dehydrogenase, G6DP) and markers of oxidative damage (advanced oxidation protein products, AOPP; lipid peroxidation, LPO). Additionally, inflammatory marker levels (IL-1, IL-6, IL-18, and TNF-α), c-miR-21, and c-miR-126 expression were analyzed. T2DM patients showed the highest oxidative damage with increased GSSG/GSH ratios, LPO, and AOPP levels. In both diabetic groups, we found that diminished SOD activity was accompanied by increased CAT and decreased GRd and G6PD activities. Diabetic patients presented with increased relative expression of c-miR-21 and decreased relative expression of c-miR-126. Overall, c-miR-21, SOD, CAT, and IL-6 had high predictive values for diabetes diagnoses. Finally, our data demonstrated that IL-6 exhibited predictive value for VC development in the studied population. Moreover, c-miR-21 and c-miR-126, along with GPx and AOPP levels, should be considered possible markers for VC development in future studies.

Hypereosinophilic syndrome (HES) is a complex multisystem disease characterized by sustained overproduction of eosinophils. A 40-year-old woman presented with digital ischemia and gangrene on her distal fingers and toes. We diagnosed HES on the basis of marked eosinophilia, accumulation of eosinophils in organs, and cutaneous eosinophilic vasculitis after having excluded all differential diagnoses. On digital subtraction angiography, occlusion of several arteries of both lower legs was noted. HES may be associated with severe vascular damage including gangrene. The occurrence of digital gangrene is a differential diagnostic challenge that should also include investigations of blood parameters, such as eosinophils.

Hypertension in midlife contributes to cognitive decline and is a modifiable risk factor for dementia. The relationship between late-life hypertension and dementia is less clear. We have investigated the relationship of blood pressure and hypertensive status during late life (after 65 years) to post-mortem markers of Alzheimer's disease (amyloid-β and tau loads); arteriolosclerosis and cerebral amyloid angiopathy; and to biochemical measures of ante-mortem cerebral oxygenation (the myelin-associated glycoprotein:proteolipid protein-1 ratio, which is reduced in chronically hypoperfused brain tissue, and the level of vascular endothelial growth factor-A, which is upregulated by tissue hypoxia); blood-brain barrier damage (indicated by an increase in parenchymal fibrinogen); and pericyte content (platelet-derived growth factor receptor β, which declines with pericyte loss), in Alzheimer's disease ( n = 75), vascular ( n = 20) and mixed dementia ( n = 31) cohorts. Systolic and diastolic blood pressure measurements were obtained retrospectively from clinical records. Non-amyloid small vessel disease and cerebral amyloid angiopathy were scored semiquantitatively. Amyloid-β and tau loads were assessed by field fraction measurement in immunolabelled sections of frontal and parietal lobes. Homogenates of frozen tissue from the contralateral frontal and parietal lobes (cortex and white matter) were used to measure markers of vascular function by enzyme-linked immunosorbent assay. Diastolic (but not systolic) blood pressure was associated with the preservation of cerebral oxygenation, correlating positively with the ratio of myelin-associated glycoprotein to proteolipid protein-1 and negatively with vascular endothelial growth factor-A in both the frontal and parietal cortices. Diastolic blood pressure correlated negatively with parenchymal amyloid-β in the parietal cortex. In dementia cases, elevated late-life diastolic blood pressure was associated with more severe arteriolosclerosis and cerebral amyloid angiopathy, and diastolic blood pressure correlated positively with parenchymal fibrinogen, indicating blood-brain barrier breakdown in both regions of the cortex. Systolic blood pressure was related to lower platelet-derived growth factor receptor β in controls in the frontal cortex and in dementia cases in the superficial white matter. We found no association between blood pressure and tau. Our findings demonstrate a complex relationship between late-life blood pressure, disease pathology and vascular function in dementia. We suggest that hypertension helps to reduce cerebral ischaemia (and may slow amyloid-β accumulation) in the face of increasing cerebral vascular resistance, but exacerbates vascular pathology., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The study aimed to assess the prevalence of subclinical cardiovascular damage in a population endemic to schistosomiasis. A cross-sectional study was conducted using colour-ultrasound assessment of abdominal and carotid arteries among adults aged >18 years living in Kome Island, Tanzania. Carotid intimal medial thickness, carotid plaque, mean abdominal aortic diameter, and presence of aneurysms were assessed. Anamnestic data on previous Patients and methods: The study aimed to assess the prevalence of subclinical cardiovascular damage in a population endemic to schistosomiasis. A cross-sectional study was conducted using colour-ultrasound assessment of abdominal and carotid arteries among adults aged >18 years living in Kome Island, Tanzania. Carotid intimal medial thickness, carotid plaque, mean abdominal aortic diameter, and presence of aneurysms were assessed. Anamnestic data on previous Schistosoma infection was collected; the actual prevalence of Schistosoma mansoni and Schistosoma haematobium was also assessed through stool and urine investigations. Results: A total of 264 participants (166 female, 98 male) were enrolled (mean age of 50±15.5 years). The history of previous schistosomiasis was 27.3%, and actual positivity for Schistosoma mansoni The significant difference in the Latero-lateral Abdominal Aortic Diameter in participants with previous Schistosomiasis history schistosomiasis, suggests the need for further investigations on aortic damage in endemic populations, independently from the positive laboratory investigations.Conclusions: The significant difference in the Latero-lateral Abdominal Aortic Diameter in participants with previous Schistosomiasis history schistosomiasis, suggests the need for further investigations on aortic damage in endemic populations, independently from the positive laboratory investigations.

Diabetic retinopathy, a microvascular disease characterized by irreparable vascular damage, neurodegeneration and neuroinflammation, is a leading complication of diabetes mellitus. There is no cure for DR, and medical interventions marginally slow the progression of disease. Microglia-mediated inflammation in the diabetic retina is regulated via CX3CR1-FKN signaling, where FKN serves as a calming signal for microglial activation in several neuroinflammatory models. Polymorphic variants of CX3CR1 , hCX3CR1 I249/M280 , found in 25% of the human population, result in a receptor with lower binding affinity for FKN. Furthermore, disrupted CX3CR1-FKN signaling in CX3CR1 -KO and FKN -KO mice leads to exacerbated microglial activation, robust neuronal cell loss and substantial vascular damage in the diabetic retina. Thus, studies to characterize the effects of hCX3CR1 I249/M280 -expression in microglia-mediated inflammation in the diseased retina are relevant to identify mechanisms by which microglia contribute to disease progression. Our results show that hCX3CR1 I249/M280 mice are significantly more susceptible to microgliosis and production of Cxcl10 and TNFα under acute inflammatory conditions. Inflammation is exacerbated under diabetic conditions and coincides with robust neuronal loss in comparison to CX3CR1 -WT mice. Therefore, to further investigate the role of hCX3CR1 I249/M280 -expression in microglial responses, we pharmacologically depleted microglia using PLX-5622, a CSF-1R antagonist. PLX-5622 treatment led to a robust (~70%) reduction in Iba1 + microglia in all non-diabetic and diabetic mice. CSF-1R antagonism in diabetic CX3CR1 -WT prevented TUJ1 + axonal loss, angiogenesis and fibrinogen deposition. In contrast, PLX-5622 microglia depletion in CX3CR1 -KO and hCX3CR1 I249/M280 mice did not alleviate TUJ1 + axonal loss or angiogenesis. Interestingly, PLX-5622 treatment reduced fibrinogen deposition in CX3CR1 -KO mice but not in hCX3CR1 I249/M280 mice, suggesting that hCX3CR1 I249/M280 expressing microglia influences vascular pathology differently compared to CX3CR1 -KO microglia. Currently CX3CR1 -KO mice are the most commonly used strain to investigate CX3CR1-FKN signaling effects on microglia-mediated inflammation and the results in this study indicate that hCX3CR1 I249/M280 receptor variants may serve as a complementary model to study dysregulated CX3CR1-FKN signaling. In summary, the protective effects of microglia depletion is CX3CR1 -dependent as microglia depletion in CX3CR1 -KO and hCX3CR1 I249/M280 mice did not alleviate retinal degeneration nor microglial morphological activation as observed in CX3CR1 -WT mice., Competing Interests: Author SG was employed by Biogen, Cambridge, MA, and is currently employed by Cerevel Therapeutics, Cambridge, MA. Author ACC is employed full-time by Biogen, Cambridge, MA. Author RR was employed full-time by Biogen, Cambridge, MA, and currently employed full-time by Third Rock Ventures, Boston, MA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Church, Rodriguez, Mendiola, Vanegas, Gutierrez, Tamayo, Amadu, Velazquez, Cardona, Gyoneva, Cotleur, Ransohoff, Kaur and Cardona.)

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular morbidity and delay the progression of kidney disease in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms underpinning these benefits are not entirely clear. More specifically, it is uncertain whether these agents exert cardiorenal protective effects through a direct action on the vascular wall. The aim of the present study was to evaluate the effects of SGLT2 inhibitors on markers of subclinical vascular damage., Methods: In total, 40 adult patients with T2DM and glomerular filtration rate (GFR) < 60 mL/min/1.73 m 2 and age- and gender-matched patients with T2DM and GFR > 60 mL/min/1.73 m 2 were consecutively enrolled. Indices of arterial stiffness (pulse wave velocity, augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (Alx@75) and central systolic, diastolic, pulse and mean pressure), carotid atherosclerosis (stenosis, intima-media thickness (cIMT) and maximal plaque thickness) and peripheral arterial disease (ankle brachial index (ABI)) were determined. The chi-squared and Mann-Whitney U-test were used to detect differences in categorical and continuous variables between groups, respectively., Results: In total, 15 patients were treated with SGLT2 inhibitors and 25 patients were not receiving these agents. Serum low-density lipoprotein cholesterol levels were lower in the former whereas other cardiovascular risk factors, the prevalence of established cardiovascular disease, anthropometric and demographic characteristics, and vital signs did not differ between the 2 groups. The AIx was lower in patients treated with SGLT2 inhibitors (21.9 ± 11.3 vs. 29.7 ± 12% in patients not treated with SGLT2 inhibitors; p < 0.05). The AIx@75 was also lower in the former (21.3 ± 10.9 and 32.6 ± 11.3%, respectively, p < 0.005). Other markers of arterial stiffness were similar in the 2 groups. In addition, markers of carotid atherosclerosis and the ABI did not differ between patients treated and not treated with SGLT2 inhibitors., Conclusions: Treatment with SGLT2 inhibitors appears to reduce arterial stiffness. Accordingly, these agents might improve cardiovascular outcomes not only in patients with T2DM and established cardiorenal disease but also in lower-risk patients.

Diabetes is one of the main risk factors for vascular damage, including endothelial dysfunction and arterial stiffness. The aim of this study was to compare selected parameters of vascular damage in patients with type 2 diabetes (T2D) in different age categories and to determine their relationship to indicators of glycometabolic control. A total of 160 patients with T2D were included in this cross-sectional study. They were divided into four age quartiles (with mean ages of 42.1 ± 4.5, 51.6 ± 1.4, 59.2 ± 3.0, and 69.8 ± 3.8, respectively). All subjects were evaluated for indicators of glycometabolic control and for arterial stiffness parameters along with markers of endothelial damage-tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF). The oldest compared to the youngest participants showed significantly increased parameters of arterial stiffness (augmentation pressure 13.4 ± 8.6 vs. 6.7 ± 4.4 mm Hg, augmentation index 26.2 ± 11.3 vs. 19.6 ± 9.2 mm Hg, aortic pulse pressure 47.7 ± 17.1 vs. 33.7 ± 10.4 mm Hg, and pulse wave velocity 11.9 (10.1-14.3) vs. 8.2 (7.7-9.8) m/s) despite having similar glycometabolic control. Arterial stiffness parameters were mainly associated with age and blood pressure. Age and systolic blood pressure were major determinants of arterial stiffness regardless of glycometabolic control. The oldest patients also had the highest levels of vWF (153.7 ± 51.9 vs. 121.7 ± 42.5 %) but the lowest levels of PAI-1 (81.8 ± 47.5 vs. 90.0 ± 44.9 ng/mL). Markers of endothelial dysfunction correlated with metabolic parameters, but did not correlate with arterial stiffness. Age and systolic blood pressure are major determinants of arterial stiffness in patients with T2D regardless of glycometabolic control, whereas an unfavorable metabolic profile is mainly related to endothelial dysfunction. These results suggest a differential contribution of cardiometabolic risk factors to vascular damage in T2D patients over their lifetime.

Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in-depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD., Methods and Results: Rats in the experimental group were intraperitoneally injected with a single dose of 60 mg/kg monocrotaline (MCT group, n = 32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n = 32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT + DAPA and CTL + DAPA groups) for a total of 4 weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4 weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P-wave duration (17.00 ± 0.53 ms, vs. 14.43 ± 0.57 ms in CTL; 14.00 ± 0.65 ms in CTL + DAPA; 14.57 ± 0.65 ms in MCT + DAPA; P < 0.05), RR interval (171.60 ± 1.48 ms, vs. 163.10 ± 1.10 ms in CTL; 163.30 ± 1.19 ms in CTL + DAPA; 163.10 ± 1.50 ms in MCT + DAPA; P < 0.05), Tpeak-Tend interval (65.93 ± 2.55 ms, vs. 49.55 ± 1.71 ms in CTL; 48.27 ± 3.08 ms in CTL + DAPA; P < 0.05), and corrected QT interval (200.90 ± 2.40 ms, vs. 160.00 ± 0.82 ms in CTL; 160.40 ± 1.36 ms in CTL + DAPA; 176.6 ± 1.57 ms in MCT + DAPA; P < 0.01) were significantly prolonged in the MCT group after 4 weeks, whereas P-wave amplitude (0.07 ± 0.0011 mV, vs. 0.14 ± 0.0009 mV in CTL; 0.14 ± 0.0011 mV in CTL + DAPA; 0.08 ± 0.0047 mV in MCT + DAPA; P < 0.05) and T-wave amplitude (0.04 ± 0.002 mV, vs. 0.13 ± 0.003 mV in CTL; 0.13 ± 0.003 mV in CTL + DAPA; P < 0.01) were decreased, and atrial 90% action potential duration (47.50 ± 0.93 ms, vs. 59.13 ± 2.1 ms in CTL; 59.75 ± 1.13 ms in CTL + DAPA; 60.63 ± 1.07 ms in MCT + DAPA; P < 0.01) and effective refractory periods (41.14 ± 0.88 ms, vs. 62.86 ± 0.99 ms in CTL; 63.14 ± 0.67 ms in CTL + DAPA; 54.86 ± 0.70 ms in MCT + DAPA; P < 0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL + DAPA; 40% in MCT + DAPA; P < 0.05) and duration of AF (30.85 ± 22.90 s, vs. 0 ± 0 s in CTL; 0.24 ± 0.76 s in CTL + DAPA; 5.08 ± 7.92 s in MCT + DAPA; P < 0.05) were significantly increased, whereas the expression levels of cardiac ion channels and calcium-handling proteins such as potassium/calcium channels and calmodulin were decreased. Mechanistically, 'NACHT, LRR, and PYD domain-containing protein 3' inflammasome-related pathway was significantly activated in the MCT group. Nevertheless, in the MCT + DAPA group, the above abnormalities were significantly improved., Conclusions: Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)