Vascular Endothelial Response Research Articles

SIRT6 inhibits endothelial-to-mesenchymal transition through attenuating the vascular endothelial inflammatory response

Endothelial-to-mesenchymal transition (EndMT) is a process of transdifferentiation in which endothelial cells gradually adopt the phenotypic characteristics of mesenchymal cells. Emerging studies demonstrate the importance of EndMT in endothelial dysfunction during inflammation. Sirtuin 6 (SIRT6), a member of the mammalian NAD+-dependent deacetylase sirtuin family, plays a critical role in cardiovascular diseases by regulating the inflammatory response. However, little is known about the effect of SIRT6 on EndMT during vascular inflammation. Therefore, we aimed to investigate the effect of SIRT6 on EndMT in endothelium-specific SIRT6 knockout (ecSIRT6-/-) mice and human umbilical vein endothelial cells (HUVECs) stimulated with inflammatory cytokines. First, we found that TNF-α and IL-1β co-treatment induced EndMT and down-regulated SIRT6 expression in HUVECs. Adenovirus-mediated SIRT6 overexpression suppressed inflammation-induced EndMT in HUVECs. In contrast, SIRT6 knockdown further promoted EndMT. Our findings also revealed that SIRT6 attenuated the inflammatory response of HUVECs. Additionally, vascular inflammation was induced by carotid artery ligation in ecSIRT6-/- mice. Results showed that the intima of ligated carotid arteries in ecSIRT6-/- mice was significantly thickened compared to that in ecSIRT6+/+ ligated mice. Moreover, endothelium-specific SIRT6 knockout promoted EndMT and increased the expression of proinflammatory cytokines in the carotid arteries of mice. These results suggest that SIRT6 inhibits EndMT through attenuating the vascular endothelial inflammatory response. These findings may have significance for reducing the occurrence of EndMT and ameliorating certain aspects of vascular inflammation.

MicroRNA-320a-3p Signatures as a Satisfactory Predictor of Acute Coronary Syndrome and Attenuates Inflammation by Targeting X-Linked Inhibitor of Apoptosis Protein

Acute coronary syndrome (ACS) is a heart disease with a high mortality rate. Recently, more and more evidence illustrated that microRNAs (miRNA) participated in regulating the occurrence of heart disease. This study aimed to detect the level of serum miR-320a-3p in patients with ACS, predict its possibility as a candidate gene for diagnosis, and explore its potential mechanism in the regulation of ACS. 139 ACS patients and 126 controls were recruited in this study. The expression level of miR-320a-3p was determined by qRT-PCR. The predictive value in ACS was assessed by receiver operating characteristic (ROC) curve. Enzyme-linked immunosorbent assay (ELISA) was used to measure the protein expression levels of inflammatory factors. The downstream targets of miR-320a-3p were verified by luciferase reporter gene assay. In ACS patients and rat models, the expression level of serum miR-320a-3p was significantly increased. ROC curve revealed that abnormal expression of miR-320a-3p was of diagnostic value for ACS. In an in vivo rat model, down-regulation of miR-320a-3p inhibited the production of von Willebrand factor (vWF), Heart fatty acid-binding protein (H-FABP), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). In other words, down-regulation of miR-320a-3p reduced rat vascular endothelial injury and inflammation. X-linked inhibitor of apoptosis protein (XIAP) was determined to be a direct target of miR-320a-3p. miR-320a-3p is useful for the diagnosis of ACS. Animal experiments confirmed that up-regulated miR-320a-3p promoted vascular endothelial injury and inflammatory response by targeting XIAP, thus promoting the development of ACS. MiR-320a-3p may be a new breakthrough in the diagnosis and treatment of ACS.

IL-6 trans-signaling regulates vascular endothelial laminin profile and inflammatory responses: Possible mechanism for immune cell recruitment during atherosclerosis?

Background and Aims: We aimed to investigate the role of IL-6 trans-signaling in regulating the release of endothelial inflammatory mediators and endothelial basement mebrane proteins, laminins. We also aimed to investigate the laminin composition in atherosclerotic plaques in relation to the immune cell content.

Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo‐ double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.

Investigation of the Multi-Target Mechanism of Guanxin-Shutong Capsule in Cerebrovascular Diseases: A Systems Pharmacology and Experimental Assessment.

Guanxin-Shutong capsule (GXSTC), a combination of Mongolian medicines and traditional herbs, has been clinically proven to be effective in treating cerebrovascular diseases (CBVDs). However, the underlying pharmacological mechanisms of GXSTC in CBVDs remain largely unknown. In this study, a combination of systems pharmacology and experimental assessment approach was used to investigate the bioactive components, core targets, and possible mechanisms of GXSTC in the treatment of CBVDs. A total of 15 main components within GXSTC were identified using high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) and a literature research. Fifty-five common genes were obtained by matching 252 potential genes of GXSTC with 462 CBVD-related genes. Seven core components in GXSTC and 12 core genes of GXSTC on CBVDs were further determined using the protein-protein interaction (PPI) and component-target-pathway (C-T-P) network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results predicted that the molecular mechanisms of GXSTC on CBVDs were mainly associated with the regulation of the vascular endothelial function, inflammatory response, and neuronal apoptosis. Molecular docking results suggested that almost all of core component-targets have an excellent binding activity (affinity < −5 kcal/mol). More importantly, in middle cerebral artery occlusion (MCAO) -injured rats, GXSTC significantly improved the neurological function, reduced the infarct volume, and decreased the percentage of impaired neurons in a dose-dependent manner. Western blotting results indicated that GXSTC markedly upregulated the expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS), while downregulating the expression of cyclooxygenase-2 (COX-2) and transcription factor AP-1 (c-Jun) in MCAO-injured rats. These findings confirmed our prediction that GXSTC exerts a multi-target synergetic mechanism in CBVDs by maintaining vascular endothelial function, inhibiting neuronal apoptosis and inflammatory processes. The results of this study may provide a theoretical basis for GXSTC research and the clinical application of GXSTC in CBVDs.

May human epididymis 4 protein play a role in the etiopathogenesis of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome?

Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is an extremely advanced form of preeclampsia. Currently, there is no parameter or marker to predict this syndrome; however, it is emphasized that vascular endothelial damage and abnormal immune responses can be the possible etiologies of HELLP syndrome. It is known that human epididymis protein 4 (HE4) is a protease inhibitor and previous studies have shown that HE4 protein levels are increased in many malignancies and inflammatory conditions. Considering that metalloproteinases may also play a role in endothelial damage, which is thought to be involved in the etiopathogenesis of HELLP syndrome, we thought that HE4 protein, which is a protease inhibitor, may be associated with vascular damage. We aimed to investigate the relationship between HELLP syndrome and HE4 protein and to identify a biomarker that can be utilized in the diagnosis of HELLP syndrome. In this study, 40 patients with HELLP syndrome and 40 healthy pregnant women with similar characteristics without HELLP syndrome were compared. When the results were evaluated, no statistically significant difference was found between serum HE4 protein levels in patients with HELLP syndrome and patients without HELLP syndrome in this study (p: 0.29). HE4 protein has no field of use in obstetrics yet. In our study, we aimed to find a new biomarker to identify patients with HELLP syndrome. However, we could not find any statistically significant difference in terms of HE4 protein levels between patients with and without HELLP syndrome. Our study is an important study as it is the first study aiming to use HE4 protein in obstetrics.

G protein-coupled estrogen receptor increases vascular endothelial inflammatory response after ovariectomized mice

To investigate the effects of calcium supplementation on the inflammatory response of vascular endothelial cells and the possible role and mechanism of G protein-coupled estrogen receptor(GPER)under the physiological conditions of estrogen deficiency(ovary removal). Forty healthy 8-week-old female C57 BL/6 mice were divided into 4 groups by random number table according to body weight, which were respectively the control group, ovarian removal group, ovarian removal high calcium group, and G1 ovarian removal high calcium group, each group ten. One week after the basal diet, the control group underwent sham surgery, and the ovaries-removed group, ovarian-removed high-calcium group, and G1 ovarian-removed high-calcium group were treated for ovarian removal. The control group and the ovary-removed group were fed basic feed(AIN-93 G, calcium content 0. 5%), the ovarian-removed high-calcium group and the G1 implanted ovarian-removed high-calcium group were fed high-calcium feed(adjusted AIN-93 G, calcium content 1. 5%). Three months later, mice in the control, ovarian-removed, and ovarian-reduced high-calcium groups were implanted with a placebo subcutaneously, and G1 ovarian-removed high-calcium groups were implanted with a GPER specific agonist G1, intervention for 28 days, under the anesthesia state, collect blood from 40 mice, isolate serum to measure vascular endothelial adhesion factor-1(VCAM-1), tumor necrosis factor-α(TNF-α), estradiol and blood calcium concentration; take aortic arch for immunization histochemical detection of transient receptor potential channel 1(TRPC1), phosphorylated-extracellular regulated kinase(p-ERK)1/2, VCAM-1 and CD68 expression levels. SPSS software performs statistical analysis and draws conclusion. The differences in weight gain between the three groups and the control group were statistically significant(P&lt;0. 05), while the differences in weight between the three groups were not statistically significant(P&gt;0. 05). There were statistically significant differences in serum estradiol levels between the three groups, the ovariectomized high calcium group, and the G1 ovariectomized group implanted with the control group(P&lt;0. 05). The difference was not statistically significant(P&gt;0. 05). The differences in serum VCAM-1 concentrations between the control group and the other three groups were statistically significant(P&lt;0. 05). The difference in serum VCAM-1 concentration was statistically significant between the ovariectomized group and the implanted G1 ovariectomized high calcium group and the ovariectomized high calcium group(P&lt;0. 05). There was no significant difference in serum VCAM-1 concentration in the group(P&gt;0. 05). There was no significant difference in TNF-α concentration between the four groups(P&gt;0. 05). By immunohistochemistry, the percentages of TRPC1, p-ERK1/2, VCAM-1, and CD68-positive cell areas in the ovarian high-calcium group were significantly higher than those in the ovarian-removed group and the G1-ovarian-removed high-calcium group. The difference was statistically significant(P&lt;0. 05), and the difference in the percentage of positive cell area between the ovarian-removed group and the G1-removed high-calcium group was not statistically significant(P&gt;0. 05). In the state of estrogen deficiency, calcium supplementation causes an increase in inflammatory response, which may be related to the change in GPER activity, and then affect the TRPC1/ERK1/2 pathway.

Ebselen reduces cigarette smoke-induced endothelial dysfunction in mice.

Background and PurposeIt is well established that both smokers and patients with COPD are at a significantly heightened risk of cardiovascular disease (CVD), although the mechanisms underpinning the onset and progression of co‐morbid CVD are largely unknown. Here, we explored whether cigarette smoke (CS) exposure impairs vascular function in mice and given the well‐known pathological role for oxidative stress in COPD, whether the antioxidant compound ebselen prevents CS‐induced vascular dysfunction in mice.Experimental ApproachMale BALB/c mice were exposed to either room air (sham) or CS generated from nine cigarettes per day, 5 days a week for 8 weeks. Mice were treated with ebselen (10 mg·kg−1, oral gavage once daily) or vehicle (5% w/v CM cellulose in water) 1 h prior to the first CS exposure of the day. Upon killing, bronchoalveolar lavage fluid (BALF) was collected to assess pulmonary inflammation, and the thoracic aorta was excised to investigate vascular endothelial and smooth muscle dilator responses ex vivo.Key ResultsCS exposure caused a significant increase in lung inflammation which was reduced by ebselen. CS also caused significant endothelial dysfunction in the thoracic aorta which was attributed to a down‐regulation of eNOS expression and increased vascular oxidative stress. Ebselen abolished the aortic endothelial dysfunction seen in CS‐exposed mice by reducing the oxidative burden and preserving eNOS expression.Conclusion and ImplicationsTargeting CS‐induced oxidative stress with ebselen may provide a novel means for treating the life‐threatening pulmonary and cardiovascular manifestations associated with cigarette smoking and COPD.

Tissue-specific endothelial cell heterogeneity contributes to unequal inflammatory responses

Endothelial cells (EC) coordinate vascular homeostasis and inflammation. In organ transplantation, EC are a direct alloimmune target. We posited that tissue specific heterogeneity of vascular EC may partly underlie the disparate organ-specific alloimmune risk. We examined the vascular endothelial response to inflammation across six primary endothelial beds from four major transplanted organs: the heart, lung, kidney and liver. First, we reanalyzed a public dataset of cardiac allograft rejection and found that endothelial inflammatory response genes were elevated in human cardiac allograft biopsies undergoing rejection compared with stable grafts. Next, the inducible inflammatory phenotypes of EC from heart, lung, kidney, and liver were characterized in vitro, focused on expression of adhesion molecules and chemokines, and recruitment of allogeneic peripheral blood mononuclear immune cells. Large vessel cardiac EC most highly upregulated VCAM-1, particularly compared with hepatic EC, supported greater leukocyte adhesion and had distinct chemokine profiles after stimulation with cytokines and complement. Differentially expressed gene candidates that are known regulators of cytokine signaling and inflammatory programming were verified in publicly available datasets of organ-specific endothelial transcriptomes. In summary, differential baseline expression of immune regulating genes may contribute to differential vascular inflammatory responses depending on organ.

Vascular endothelial and smooth muscle cell galvanotactic response and differential migratory behavior

Chronic disease or injury of the vasculature impairs the functionality of vascular wall cells particularly in their ability to migrate and repair vascular surfaces. Under pathologic conditions, vascular endothelial cells (ECs) lose their non-thrombogenic properties and decrease their motility. Alternatively, vascular smooth muscle cells (SMCs) may increase motility and proliferation, leading to blood vessel luminal invasion. Current therapies to prevent subsequent blood vessel occlusion commonly mechanically injure vascular cells leading to endothelial denudation and smooth muscle cell luminal migration. Due to this dichotomous migratory behavior, a need exists for modulating vascular cell growth and migration in a more targeted manner. Here, we examine the efficacy of utilizing small direct current electric fields to influence vascular cell-specific migration (“galvanotaxis”). We designed, fabricated, and implemented an in vitro chamber for tracking vascular cell migration direction, distance, and displacement under galvanotactic influence of varying magnitude. Our results indicate that vascular ECs and SMCs have differing responses to galvanotaxis; ECs exhibit a positive correlation of anodal migration while SMCs exhibit minimal change in directional migration in relation to the electric field direction. SMCs exhibit less motility response (i.e. distance traveled in 4 h) compared to ECs, but SMCs show a significantly higher motility at low electric potentials (80 mV/cm). With further investigation and translation, galvanotaxis may be an effective solution for modulation of vascular cell-specific migration, leading to enhanced endothelialization, with coordinate reduced smooth muscle in-migration.

Особенности изменений стресс-регулирующих систем у подростков с сердечно-сосудистой патологией при эндотелиальной дисфункции

Relevance. Endothelial dysfunction serves as a starting mechanism for any vascular pathology and its progression. The state of endothelial function is greatly influenced by stress, however, the study of the features of the functioning of stress-regulating systems in adolescents with cardiovascular disorders has practically not been studied. Objective: to investigate stress-regulating system changes in adolescents with cardiovascular disease at endothelial dysfunction. Materials and methods. A total of 73 adolescents (49 boys and 24 girls) with cardiovascular disease (CVD) aged 12–18 were surveyed. The adolescents were divided into 3 groups: those with normal endothelial function, those with endothelial dysfunction and those with paradoxical vascular endothelial response. Stress regulation is dominated by stress- realizing and stress-limiting systems. The state of stress-realizing systems was assessed by the level of cortisol, malondialdehyde, carbonylated proteins (CP) in blood serum and catecholamines (CA) in urine; stress-limiting systems — by the level of glutathione peroxidase (GPO), superoxide dismutase (SOD), serotonin in the blood and melatonin in urine. Results. In adolescents with endothelial dysfunction and paradoxical vascular endothelial response, there was a regulatory imbalance of key antioxidant enzymes (SOD and GPO) and a decrease in serotonin levels. In endothelial vascular dysfunction, changes in stress-regulatory systems are more pronounced in girls. The revealed correlation relations of the studied indicators in adolescents with normal function and vascular endothelium dysfunction emphasize strong links between monoamines (CA and melatonin), enzymatic (GPO) tension and activation of non-enzymatic (melatonin) links of antioxidant system. Conclusion. In adolescents with a non-inflammatory pathology of CVD, endothelial function depends on the activation and interaction of stress-regulating systems. With vascular endothelial dysfunction, changes in the content of monoamines and indicators of the pro- and antioxidant systems have gender differences, indicating stress-limiting stress and activation of stress-realizing systems in girls. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the author. Key words: adolescents, cardiovascular system, endothelial function, stresslimiting indicators, stressrealizing indicators.

Vascular endothelial function is improved after active mattress use

Active mattresses are used to prevent, treat and relieve pressure ulcers (PU) by intermittent contact pressure/relief. However, no studies have directly assessed the vascular endothelial response to long-term active mattress use. This study investigated the hypothesis that eight weeks use of an active mattress would lead to improvements in vascular endothelial function in healthy participants. Physiological parameters of baseline skin temperature (BskT), resting blood flow (RBF) and endothelial function as measured using post-occlusive reactive hyperaemia (PORH), were assessed at baseline (week 0); following eight weeks of sleeping on an active mattress, and after an eight week washout period (at week 16). We recruited 10 healthy participants (four male, age 52.7±8.5 years, six female age 51.8±17.5 years). Following active mattress use RBF, PORH and BskT at the hallux pulp increased by 336%, 197% and 3.5°C, respectively. Mean values increased from 24.3±38.3 perfusion units to 106.0±100.3 perfusion units (p=0.021) and from 13,456±10,225 to 40,252±23,995 perfusion units x seconds (p=0.003) and from 22.9±2.5°C to 26.4±1.9°C (p<0.001), respectively. Active mattress use for eight weeks leads to significant improvements in RBF, PORH, and BskT. These results suggest that active mattress use can improve endothelial function. Future research is required to explore the potential of active mattress use in the treatment and management of diseases and conditions that would benefit from an improved endothelial function.

Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis.

Stem cells have been confirmed to be involved in the occurrence and development of diabetic retinopathy; however, the underlying mechanisms remain unclear. In this study, we used Citespace software to visually analyze 552 articles exploring the stem cell-based treatment of diabetic retinopathy over the past 20 years, which were included in the Web of Science Core Collection. We found the following: (1) a co-citation analysis of the references cited by all 552 articles indicated 15 clusters. In cluster #0, representing the stem cell field, some highly cited landmark studies emerged between 2009–2013. For example, endothelial progenitor cells and diabetic retinopathy gradually received the full attention of scholars, in terms of their relationship and therapeutic prospects. Some researchers also verified the potential of adipose-derived stem cells to differentiate into stable retinal perivascular cells, using a variety of animal models of retinal vascular disease. All of these achievements provided references for the subsequent stem cell research. (2) An analysis of popular keywords among the 552 articles revealed that, during the past 20 years, a relative increase in basic research articles examining stem cells and endothelial progenitor cells for the treatment of diabetic retinopathy was observed. The contents of these articles primarily involved the expression of vascular endothelial growth factor, vascular regeneration, oxidative stress, and inflammatory response. (3) A burst analysis of keywords used in the 552 articles indicated that genetic and cytological research regarding the promotion of angiogenesis was an issue of concern from 2001 to 2012, including several studies addressing the expression of various growth factor genes; from 2014 to 2020, mouse models of diabetic retinopathy were recognized as mature animal models, and the most recent research has focused on macular degeneration, macular edema, neurodegeneration, and inflammatory changes in diabetic animal models. (4) Globally, the current authoritative studies have focused on basic research towards the stem cell treatment of diabetic retinopathy. Existing clinical studies are of low quality and have insufficient evidence levels, and their findings have not yet been widely accepted in clinical practice. Major challenges during stem cell transplantation remain, including stem cell heterogeneity, cell delivery, and the effective homing of stem cells to damaged tissue. However, clinical trials examining potential stem cell-based treatments of diabetic retinopathy, including the use of pluripotent stem cells, retinal pigment epithelial cells, bone marrow mesenchymal stem cells, and endothelial progenitor cells, are currently ongoing, and high-quality clinical evidence is likely to appear in the future, to promote clinical transformation.

Chromogranin A (CGA)-derived polypeptide (CGA47–66) inhibits TNF-α-induced vascular endothelial hyper-permeability through SOC-related Ca2+ signaling

CGA1−78 (Vasostatin-1, VS-1) a N-terminal Chromogranin A (CGA)-derived peptide, has been shown to have a protective effect against TNF-α-induced impairment of endothelial cell integrity. However, the mechanisms of this effect have not yet been clarified. CGA47−66 (Chromofungin, CHR) is an important bioactive fragment of CGA1−78. The present study aims to explore the protective effects of CHR on the vascular endothelial cell barrier response to TNF-α and its related Ca2+ signaling mechanisms. EA.hy926 cells were used as a vascular endothelial culture model. The synthetic peptides CHR and CGA4−16 were assessed for their ability to suppress TNF-α-induced EA.hy926 cells hyper-permeability through Transwell® and TEER assays. Changes in [Ca2+]i were measured through confocal laser scanning microscopy. SOC channel currents (Isoc) were measured via patch-clamp analysis. RT-PCR and western blot were used to analyze mRNA and protein expression of the transient receptor potential channels TRPC1 and TRPC4, respectively. FITC and rhodamine-phalloidin fluorescence were used to assess cell morphology and the distribution of MyPT-1 and F-actin. Compared to untreated cells, TNF-α increased the permeability of EA.hy926 cells that was inhibited by pre-treatment with CHR (10–1000 nM) in concentration-dependent manner, and the effect was most obvious at 100 nM, but CGA4−16 (100 nM) had no effect. TNF-α treatment increased the phosphorylation of MyPT-1 and stress fiber formation. CHR (10–1000 nM) pretreatment inhibited the cytoskeletal rearrangements and increased [Ca2+]i in response to TNF-α treatment. CHR also reduced TRPC1 expression following TNF-α induction. Similar to SOC inhibitor 2-APB, CHR suppressed IP3 mediated SOC activation. These findings suggest that CHR inhibits TNF-α-induced Ca2+ influx and protects the barrier function of vascular endothelial cells, and that these effects are related to the inhibition of SOC and Ca2+ signaling by CHR.

KLF4 alleviates cerebral vascular injury by ameliorating vascular endothelial inflammation and regulating tight junction protein expression following ischemic stroke

BackgroundAlthough inflammatory cell adhesion molecules (CAMs) and anti-inflammation factor Kruppel-like transcription factor (KLF) 4 have all been reported to be induced after cerebral ischemic stroke (CIS), the close temporal and spatial relationship between expressions of CAMs and KLF4 following CIS and whether and how CAMs and KLF-4 contribute to the development of CIS-induced vascular injury are still unclear.MethodsHere, we first examined the correlation between serum levels of CAMs/KLF4 and infarct volume in acute CIS patients. Then, we determined the relationship between CAMs and KLF4 in mice after focal cerebral ischemia. Finally, we investigated the mechanism of KLF4 in protecting against oxygen-glucose deprivation-induced brain endothelial cell injury.ResultsOur results demonstrated that patients with moderate to severe CIS had higher serum levels of three CAMs including E-selectin, inter-cellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) but lower levels of KLF4 at 48 h after an acute event as compared to patients with minor CIS. The expression levels of three CAMs as well as KLF4 all correlated well with the infarct volume in all the CIS subjects at that time. Although the expressions of three CAMs and KLF4 were all induced in the ischemic hemisphere following focal cerebral ischemia, the peak timing and distribution patterns of their expression were different: the induction of KLF4 lagged behind that of the CAMs in the ischemic penumbra; furthermore, the dual immunofluorescent studies displayed that high expression of KLF4 was always associated with relatively less cerebral vascular endothelial inflammation response in the ischemic hemisphere and vice versa. Mechanistic analyses revealed that KLF4 alleviated CIS-induced cerebral vascular injury by regulating endothelial expressions of CAMs, nuclear factor-kB, and tight junction proteins.ConclusionsThese data indicate that KLF4 confers vascular protection against cerebral ischemic injury, suggesting that circulating CAMs and KLF4 might be used as potential biomarkers for predicting the prognosis of acute ischemic stroke and also providing a new proof of concept and potential targets for future prevention and treatment of CIS.

Acute blood glucose and vascular endothelial responses to passive heating in individuals with type 2 diabetes

IntroductionInsulin resistance and hyperglycemia predispose individuals with type 2 diabetes mellitus (T2DM) to endothelial dysfunction and a greater risk of cardiovascular diseases. Numerous animal studies suggest that heat exposure improves glucose control and human studies suggest that it improves markers of vascular health. However, the physiological responses to heat exposure remain understudied in individuals with T2DM, particularly within a therapeutic context.ObjectiveTo characterize blood glucose and vascular endothelial responses to heat exposure in T2DM and determine if heating acutely improves glucose control and endothelial function in this population.MethodsOn separate randomized days, six adults (2 males/4 females, 60 ± 12 years) with T2DM (≥1 year, HbA1c: 7.0 ± 0.5%, fasting glucose: 7.79 ± 1.13 mmol/L) were immersed in control (34°C, 90 minutes) or hot (40–41°C, core temperature ≥38.5°C for 60 minutes) water. Participants were fasted (12 hours) and withheld anti‐diabetic medication (≥24 hours). Blood glucose and insulin as well as brachial artery shear rates were measured at baseline, during immersion and 45–60 minutes after immersion. Brachial artery flow‐mediated dilation (FMD) was measured at baseline and 45 minutes after immersion. Blood glucose control was evaluated during an oral glucose tolerance test (OGTT, 75 g) 60 minutes after immersion. Core (Tcore, rectal) and mean skin (Tskin) temperatures, heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures were measured throughout the protocol.ResultsCompared to control, hot water immersion increased Tcore (+1.44°C [1.05, 1.83], P&lt;0.01), Tskin (+2.36°C [1.21, 3.51], P&lt;0.01), HR (+35 bpm [26, 43], P&lt;0.01), and decreased DBP (−7 mmHg [−2, −13], P&lt;0.01) and SBP (−9 mmHg [−1, −16], P=0.03). Hot water immersion increased antegrade (+71 s−1 [35, 107], P&lt;0.01) and decreased retrograde (−15 s−1 [0.9, 3], P=0.06) shear rates. Nonetheless, FMD was unchanged during both control (−0.74% [−4.33, 2.86], P=0.81) and hot (−1.93% [−5.53, 1.66], P=0.30) water immersion. Blood glucose decreased progressively throughout the control protocol (−1.3 mmol/L [−0.8, −1.9], P&lt;0.01), whereas hot water immersion attenuated this decrease (+0.1 mmol/L [−0.5, +0.6], P=0.93). Hot water immersion did not alter glucose (P=0.17) and insulin (P=0.99) area under the curve during the OGTT.ConclusionThese preliminary results suggest that the physiological responses associated with heat exposure do not translate into acute improvements in blood glucose control or brachial artery endothelial function in individuals with T2DM.Support or Funding InformationCardiometabolic Health, Diabetes and Obesity Research Network and Diabetes Quebec.

Effects of low versus standard pressure pneumoperitoneum on renal syndecan-1 shedding and VEGF receptor-2 expression in living-donor nephrectomy: a randomized controlled study

BackgroundLaparoscopic nephrectomy is a preferred technique for living kidney donation. However, positive-pressure pneumoperitoneum may have an unfavorable effect on the remaining kidney and other distant organs due to inflamed vascular endothelium and renal tubular cell injury in response to increased systemic inflammation. Early detection of vascular endothelial and renal tubular response is needed to prevent further kidney injury due to increased intraabdominal pressure induced by pneumoperitoneum. Transperitoneal laparoscopic living donor nephrectomy represented a human model of mild increasing intraabdominal pressure. This study aimed to assess the effect of increased intraabdominal pressure on vascular endothelium and renal tubular cells by comparing the effects of low and standard pressure pneumoperitoneum on vascular endothelial growth factor receptor-2 (VEGFR-2) expression and the shedding of syndecan-1 as the early markers to a systemic inflammation.MethodsWe conducted a prospective randomized study on 44 patients undergoing laparoscopic donor nephrectomy. Subjects were assigned to standard (12 mmHg) or low pressure (8 mmHg) groups. Baseline, intraoperative, and postoperative plasma interleukin-6, syndecan-1, and sVEGFR-2 were quantified by ELISA. Syndecan-1 and VEGFR-2 expression were assessed immunohistochemically in renal cortex tissue. Renal tubule and peritubular capillary ultrastructures were examined using electron microscopy. Perioperative hemodynamic changes, end-tidal CO2, serum creatinine, blood urea nitrogen, and urinary KIM-1 were recorded.ResultsThe low pressure group showed lower intra- and postoperative heart rate, intraoperative plasma IL-6, sVEGFR-2 levels and plasma syndecan-1 than standard pressure group. Proximal tubule syndecan-1 expression was higher in the low pressure group. Proximal-distal tubules and peritubular capillary endothelium VEGFR-2 expression were lower in low pressure group. The low pressure group showed renal tubule and peritubular capillary ultrastructure with intact cell membranes, clear cell boundaries, and intact brush borders, while standard pressure group showed swollen nuclei, tenuous cell membrane, distant boundaries, vacuolizations, and detached brush borders.ConclusionThe low pressure pneumoperitoneum attenuated the inflammatory response and resulted in reduction of syndecan-1 shedding and VEGFR-2 expression as the renal tubular and vascular endothelial proinflammatory markers to injury due to a systemic inflammation in laparoscopic nephrectomy.Trial registrationClinicalTrials.gov NCT:03219398, prospectively registered on July 17th, 2017.

Two variants in vascular endothelial growth factor gene affect response to treatment for age-related macular degeneration in the Israeli population

Two variants in vascular endothelial growth factor gene affect response to treatment for age-related macular degeneration in the Israeli population

Vascular endothelial function is improved after active mattress use.

Active mattresses are used to prevent, treat and relieve pressure ulcers (PU) by intermittent contact pressure/relief. However, no studies have directly assessed the vascular endothelial response to long-term active mattress use. This study investigated the hypothesis that eight weeks use of an active mattress would lead to improvements in vascular endothelial function in healthy participants. Physiological parameters of baseline skin temperature (BskT), resting blood flow (RBF) and endothelial function as measured using post-occlusive reactive hyperaemia (PORH), were assessed at baseline (week 0); following eight weeks of sleeping on an active mattress, and after an eight week washout period (at week 16). We recruited 10 healthy participants (four male, age 52.7±8.5 years, six female age 51.8±17.5 years). Following active mattress use RBF, PORH and BskT at the hallux pulp increased by 336%, 197% and 3.5ºC, respectively. Mean values increased from 24.3±38.3 perfusion units to 106.0±100.3 perfusion units (p=0.021) and from 13,456±10,225 to 40,252±23,995 perfusion units x seconds (p=0.003) and from 22.9±2.5ºC to 26.4±1.9ºC (p<0.001), respectively. Active mattress use for eight weeks leads to significant improvements in RBF, PORH, and BskT. These results suggest that active mattress use can improve endothelial function. Future research is required to explore the potential of active mattress use in the treatment and management of diseases and conditions that would benefit from an improved endothelial function.

Marine-Derived Omega-3 Polyunsaturated Fatty Acids and Heart Failure: Current Understanding for Basic to Clinical Relevance.

Heart failure (HF) is a rapidly growing global public health problem. Since HF results in high mortality and re-hospitalization, new effective treatments are desired. Although it remains controversial, omega 3 polyunsaturated fatty acids (n-3 PUFAs), such as the eicosapentaenoic acid and docosahexaenoic acid, have been widely recognized to have benefits for HF. In a large-scale clinical trial regarding secondary prevention of HF by n-3 PUFA (GISSI-HF trial), the supplementation of n-3 PUFA significantly reduced cardiovascular mortality and hospitalization. Other small clinical studies proposed that n-3 PUFA potentially suppresses the ventricular remodeling and myocardial fibrosis, which thereby improves the ventricular systolic and diastolic function both in ischemic and non-ischemic HF. Basic investigations have further supported our understanding regarding the cardioprotective mechanisms of n-3 PUFA against HF. In these reports, n-3 PUFA has protected hearts through (1) anti-inflammatory effects, (2) intervention of cardiac energy metabolism, (3) modification of cardiac ion channels, (4) improvement of vascular endothelial response, and (5) modulation of autonomic nervous system activity. To clarify the pros and cons of n-3 PUFA on HF, we summarized recent evidence regarding the beneficial effects of n-3 PUFA on HF both from the clinical and basic studies.