Vascular Cell Adhesion Molecule-1 Levels Research Articles

Benzo[b]fluoranthene damages coronary artery and affects atherosclerosis markers in mice and umbilical vein endothelial cells

Polycyclic aromatic hydrocarbons (PAHs) exposure is associated with cardiovascular diseases. Toxic effects of PAHs are diverse, while cardiovascular consequences of benzo[b]fluoranthene (B[b]F) are unclear. Here, we reported the impacts of B[b]F on coronary artery and atherosclerosis markers both in mice and umbilical vein endothelial EAhy.926 cells. In mice, we found that B[b]F decreases heart-to-body weight ratio, affects aortic physiology, elevates serum low-density lipoprotein and total cholesterol, increases aortic levels of collagen fiber and atherosclerotic marker vascular cell adhesion molecule-1 (VCAM-1), and downregulates oxidative stress related nuclear factor erythroid 2-related factor 2 (Nrf2). In EAhy.926 cells, we showed that B[b]F inhibits cell proliferation and migration in a dose-dependent manner, induces cell cycle arrest and apoptosis, increases reactive oxygen species, upregulates VCAM-1 level, and suppresses expression of Nrf2. Taken together, our findings reveal that B[b]F exposure may contribute to coronary artery damage and potentially induce atherosclerosis, possibly via the Nrf2-related signaling pathways.

Adhesion molecules and atherosclerosis in ankylosing spondylitis: implications for cardiovascular risk.

Ankylosing Spondylitis (AS) stands as a chronic inflammatory arthritis within the spondyloarthritis spectrum, notably increasing cardiovascular (CV) risk and mortality through accelerated atherosclerosis compared to the non-affected population. While evidence in some studies supports a higher cardiovascular morbidity in AS patients, results from other studies reveal no significant disparities in atherosclerotic markers between AS individuals and healthy controls. This discrepancy may arise from the complex interaction between traditional CV risk factors and AS inflammatory burden. Endothelial dysfunction, a recognized antecedent of atherosclerosis prevalent among most individuals with AS, demonstrates the synergistic impact of inflammation and conventional risk factors on endothelial injury, consequently hastening the progression of atherosclerosis. Remarkably, endothelial dysfunction can precede vascular pathology in AS, suggesting a unique relationship between inflammation, atherosclerosis, and vascular damage. The role of adhesion molecules in the development of atherosclerosis, facilitating leukocyte adherence and migration into vascular walls, underscores the predictive value of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels for cardiovascular events. Despite significant progress in comprehending the pathogenesis of AS and its associated cardiovascular implications, the interplay among inflammation, endothelial dysfunction, and atherosclerosis remains partially elucidated. Investigations into the efficacy of therapeutic approaches involving angiotensin receptor blockers and statins have demonstrated reduced cardiovascular risk in AS patients, underscoring the imperative for additional research in this domain.

Pathogenesis of respiratory failure in COVID-19 due to coagulopathy and endothelial dysfunction

Respiratory failure is known to be the main clinical manifestation of COVID-19. However, the mechanism of its development has not been sufficiently studied. The originality of the study is that for the first time, coagulation, fibrinolysis and endothelial dysfunction indicators were studied depending on the SpO2/FiO2 index in patients with COVID-19.The aim of the work. To assess the role of impaired activity of the blood coagulation system and the development of endothelial dysfunction in patients with COVID-19 in the pathogenesis of respiratory failure.Methods. The study included 134 patients infected with SARS-CoV-2 virus having varying severity of the clinical picture. They were divided into three groups according to the SpO2/FiO2 index. We determined the number of venous blood cells and studied the level of transferrin (TF), D-dimer, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the blood serum.Results. The study revealed that the tissue factor content increased by 24 % in patients of the third group compared to the first. The PAI-1 level was high in the second group and significantly decreased in the third (p < 0.001). An increase in the D-dimer level was recorded in the second and third groups. The levels of ICAM-1 and VCAM-1 molecules increased significantly in the third group of patients (p = 0.021 and p = 0.028, respectively). A moderate positive correlation was found between the SpO2/FiO2 index and the VCAM-1 level (p < 0.001), a weak positive correlation with PAI-1 (p = 0.012), and a weak negative correlation with TF (p = 0.027).Conclusion. Respiratory failure in patients with COVID-19 is caused by disorders in the hemostasis and fibrinolysis systems, as evidenced by an increase in the level of tissue factor and D-dimer, “consumption” of tissue activator and plasminogen activator inhibitor. Developing endothelial dysfunction, accompanied by increased secretion of adhesion molecules, aggravates the pathogenesis of respiratory failure.

Endothelial Dysfunction in Children with Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome

Background Children with frequently relapsing (FR) or steroid-dependent (SD) nephrotic syndrome (NS) show endothelial dysfunction and risk of endothelial injury during relapses, increasing the risk of accelerated atherosclerosis and adverse cardiovascular events. This study examines the plasma levels of markers of endothelial dysfunction [sE-selectin and vascular cell adhesion molecule-1 (VCAM-1)] in children aged 1–16 years with FRNS and SDNS in relapse. Materials and Methods Fifty-six children with FRNS and SDNS between 1 and 16 years were enrolled at the time of relapse and followed till six weeks of steroid-induced remission. Markers of endothelial dysfunction (sE-selectin and VCAM-1) in plasma were measured in these children and in an equal number of controls. Results Plasma sE-selectin and VCAM-1 levels were significantly raised during relapse, declined after six weeks of steroid-induced remission, and became comparable to controls (p < 0.0001). We found high serum total cholesterol and triglycerides levels during relapse that remained elevated even after steroid-induced remission as compared to controls (p < 0.0001). Raised levels of these markers confirm endothelial dysfunction in FRNS and SDNS patients. Conclusion Children with FRNS and SDNS had endothelial dysfunction during relapse, which was largely dependent upon disease activity.

Low brain-derived neurotrophic factor and high vascular cell adhesion molecule-1 levels are associated with chronic kidney disease in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (DM) have a high prevalence of chronic kidney disease (CKD). Energy imbalance and inflammation may be involved in the pathogenesis of CKD. We examined the effects of brain-derived neurotrophic factor (BDNF) and vascular cell adhesion molecule-1 (VCAM-1) on CKD in patients with type 2 DM. Patients with type 2 DM were enrolled for this cross-sectional study. Fasting serum was prepared to measure the BDNF and VCAM-1 levels. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 was used as the criterion for identifying patients with CKD. Of the 548 enrolled participants, 156 had CKD. Patients with CKD exhibited significantly lower BDNF (median of 21.4 ng/mL, interquartile range [IQR]: 17.0-27.0 ng/mL vs. median of 25.9 ng/mL, IQR: 21.0-30.4 ng/mL, P <0.001) and higher VCAM-1 (median of 917 ng/mL, IQR: 761-1172 ng/mL vs. median of 669 ng/mL, IQR: 552-857 ng/mL, P <0.001) levels than those without CKD. Serum BDNF levels were inversely correlated with VCAM-1 levels (Spearman's rank correlation coefficient = -0.210, P <0.001). The patients were divided into four subgroups based on median BDNF and VCAM-1 levels (24.88 ng/mL and 750 ng/mL, respectively). Notably, patients in the high VCAM-1 and low BDNF group had the highest prevalence (50%) of CKD. Multivariate logistic regression revealed a significantly higher odds ratio (OR) of CKD in the high VCAM-1 and low BDNF group (OR = 3.885, 95% CI: 1.766-8.547, P <0.001), followed by that in the high VCAM-1 and high BDNF group (OR = 3.099, 95% CI: 1.373-6.992, P =0.006) compared with that in the low VCAM-1 and high BDNF group. However, the risk of CKD in the low VCAM-1 and low BDNF group was not significantly different from that in the low VCAM-1 and high BDNF group (P =0.266). CKD in patients with type 2 DM is associated with low serum BDNF and high VCAM-1 levels. BDNF and VCAM-1 have a synergistic effect on CKD. Thus, BDNF and VCAM-1 can be potential biomarkers for CKD risk stratification in patients with type 2 DM.

Construction of competitive endogenous RNA regulatory network and clinical verification for repeated implantation failure

Objective: To construct a repetitive implantation failure (RIF)-related competitive endogenous RNA (ceRNA) regulatory network and validate with clinical samples. Methods: RIF-related long non-coding RNA (lncRNA), microRNA (miRNA) and messenger RNA (mRNA) from the high-throughput gene expression omnibus (GEO) database Expression profile data set were obtained to construct a ceRNA regulatory network of lncRNA-miRNA-mRNA. At the same time, weighted gene co-expression network analysis (WGCNA) was used to explore hub genes in the network. This retrospective study collected RIF patients and controls (at least one pregnancy history after assisted conception) who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) for assisted pregnancy from 2020 to 2021 at the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University. In the endometrial tissue of patients with 1 pregnancy history, real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression levels of RIF-related hub genes, and Western blotting and immunohistochemistry were used to verify protein expression levels of vascular cell adhesion molecule-1 (VCAM1). Results: A RIF-related ceRNA regulatory network consisting of 32 lncRNAs, 31 miRNAs and 88 mRNAs was constructed, and 7 RIF-related hub genes were identified using WGCNA. By intersecting 88 mRNAs and hub genes in the ceRNA network, two RIF-related key genes were obtained, i.e., VCAM1 and interleukin-2 receptor α (interleukin-2 receptor α, IL-2RA). In clinical verification, the ages of the control group and RIF group [M (Q1, Q3)] were 26.50 (25.00, 34.00) and 30.50 (25.75, 35.25) years old, respectively (P>0.05). Compared with the control group, the mRNA [0.30 (0.15, 0.42) vs 0.99 (0.69, 1.34), P=0.001] and protein expression [0.44 (0.16, 1.27) vs 2.39 (1.58, 2.58), P<0.001] of VCAM1 in the endometrium of the RIF group were both reduced. Conclusions: This study uses bioinformatics analysis methods to construct a RIF-related ceRNA regulatory network, and it is confirmed through clinical samples that the expression level of VCAM1 in the endometrial tissue of RIF patients is significantly reduced.

Extensive study of CCN4, VCAM-1, MMP-3, and GM-CSF as reliable markers for disease activity in rheumatoid arthritis

BackgroundThe involvement of Wnt-1-induced secreted protein-1 (WISP1/CCN4) in several inflammatory reaction has recently been proposed. Nevertheless, this protein's involvement in rheumatoid arthritis (RA) remains debated. Associations between poorly diagnosed RA and several classical markers derived from demography and biochemistry have been reported. AimWe sought to investigate the reliability and effectiveness of serum concentrations of CCN4, vascular cell adhesion molecule-1 (VCAM-1), matrix melloprotenase-3 (MMP-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in monitoring and predicting RA and bone damage, and their correlation with RA disease course. MethodsThe study analyzed 128 patients with RA, comprising 68 newly diagnosed and 60 previously diagnosed patients, as well as 60 controls. Biomarker levels were measured with enzyme linked immuno-sorbent assays. Routine laboratory parameters such as serological, clinical, biochemical, and hematological parameters were additionally measured. Demography, anthropometry, and clinical symptom data were collected through interviews and a questionnaire. The joint disease activity score 28 (DAS28) was used to determine disease activity. ResultsConcentrations of four biomarkers were significantly higher in the RA group than the healthy controls. Elevated biomarker concentrations were also observed in patients with high, rather than moderate or low, DAS28-ESR activity status, except for monocyte count, hematocrit (%), and urea level. Furthermore, CCN4 level positively correlated with VCAM-1, MMP-3, and GM-CSF levels, DA-S28-CRP and DAS28-ESR. The levels of three predictive markers, CCN4, VCAM-1, and MMP-3, were elevated in non-treated patients, whereas GM-CSF level showed no difference. The highest area under the curve was 73.3% for CCN4, with 93.3% sensitivity and 64.7% specificity. ConclusionOur data suggest that CCN4 can be reliably used to indicate activity and therapeutic response associated with RA, thus facilitating earlier RA diagnosis.

Differences in T cell-associated serum markers between ischemic cardiomyopathy and dilated cardiomyopathy.

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) have similar clinical manifestations but differ in pathogenesis. We aimed to identify T cell-associated serum markers that can be used to distinguish between ICM and DCM. We identified differentially expressed genes (DEGs) with transcriptome sequencing data in GSE116250, and then conducted enrichment analysis of DEGs in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Protein-protein interaction (PPI) networks were used to analyze the relationship between T cells-related genes and identify hub genes. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect T cell-associated proteins in serum, and receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of these serum markers. Using the limma package and Venn plots, we found that the non-failing donors (NFD) and DCM groups shared many of the same DEGs and DEGs-enriched functions compared to the ICM group, which were involved in T cell activation and differentiation, among other functions. Subsequently, the immune cell score showed no difference between NFD and DCM, but they were significantly different from ICM patients in CD8 T cells CD4 T cells memory resting and activated, T cells follicular helper, and M1 macrophage. After analyzing T cell-associated DEGs, it was found that 4 DEGs encoding secreted proteins were highly expressed in the ICM group compared with the NFD and DCM groups, namely chemokine (C-C motif) ligand 21 (CCL21), interleukin (IL)-1β, lymphocyte-activation gene 3 (LAG3), and vascular cell adhesion molecule-1 (VCAM-1). Importantly, the serum levels of CCL21, IL-1β, LAG3, and VCAM-1 in ICM patients were all significantly higher than those in DCM patients. The ROC curves showed that the area under the curve (AUC) values of serum CCL21, IL-1β, LAG3, and VCAM-1 were 0.775, 0.868, 0.934, and 0.903, respectively. We have identified four T cell-associated serum markers, CCL21, IL-1β, LAG3, and VCAM-1, as potential diagnostic serum markers that differentiate ICM from DCM.

Comparison of serum Vascular Cell Adhesion Molecule (VCAM) level among epithelial ovarian cancer patients and healthy women.

To compare serum vascular cell adhesion molecule levels among ovarian cancer patients of different standardised grades, and in relation to healthy controls. The case-control study was conducted from 6.2.2018 to 1.8.2021 after approval form the ethics review board of the University of Health Sciences, Lahore, Pakistan, and comprised females aged 20-70 years diagnosed with ovarian cancer and tentatively planned for surgical procedures in group A, and healthy controls in group B. From all the subjects, 2.5ml blood was taken in a green-top tube. The tubes were centrifuged, and the serum was separated within an hour of sample collection. The Eppendorf tubes were labelled and stored at -20°C. The samples were thawed, and, following the manual protocol, they were subjected to vascular cell adhesion molecule enzyme-linked immunosorbent assay. Cancer antigen 125 values before surgery and 6-8 months post-surgery were recorded from available laboratory reports. Also, group A was categorised in line with the International Federation of Gynaecology and Obstetrics stage classification. Data was analysed using SPSS 24. Of the 80 female subjects, 40(50%) were group A cases and 40(50%) were group B controls. The overall mean age was 48±12 years. Overall, 55(68.7%) women were aged <55 years and 25(31.3%) were aged >55 years. Within group A, 20(50%) had cancer stage I-II and 20(50%) had stage III-IV. Overall median vascular cell adhesion molecule was 72.40ug/L (interquartile range: 1857.40ug/L), with 71.15ug/L (interquartile range: 616.60ug/L) in group A and 74.10ug/L (interquartile range: 1848.70ug/L) in group B. Significant correlation was found between cancer stage and vascular cell adhesion molecule level (rho=0.73; p=0.003). There was a decreased level of vascular cell adhesion molecule level in epithelial ovarian cancer cases compared to healthy controls. A positive association was observed between ovarian cancer stage and vascular cell adhesion molecule level.

An evaluation of inflammatory and endothelial dysfunction markers as determinants of peripheral arterial disease in those with diabetes mellitus

The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation. The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy. Therefore, current study is aimed to evaluate the inflammatory and endothelial dysfunction markers with their correlation to biomarkers that can help for in-time diagnosis and efficient prognosis of developing diabetes-associated PAD. Enzyme-linked immunosorbent assay was used to evaluate the interlukin-6, interlukin-8, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) in PAD with diabetes group, diabetic group and healthy individual group while biomarkers were measured by kit method. It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16). The overall means for the parameters, IL-6, IL-8, ICAM, VCAM, urea, S/creatinine, CK-MB, AST, ALT, cholesterol, triglyceride, HDL, LDL, PT, aPTT, INR, HbA1C, and CRP within all groups were significantly (P < 0.05) different from each other. Therefore, it was concluded that the change in IL-6, IL-8, ICAM and VCAM can serve as an accurate diagnostic indicator and successful treatment.

Study of Adhesion Molecules in Diabetes Mellitus Type2 Iraqi Patients with Dyslipidemia

Background: Cell adhesion molecules are protein entities that are located on the cell surface. The vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression is related to type 2 diabetes mellitus (T2DM) with dyslipidemia. Objectives: To determine the levels of VCAM-1 and ICAM-1 in T2DM patients with dyslipidemia and to explore the relationship between VCAM-1 and ICAM-1 and the development of dyslipidemia in T2DM patients. Patients and methods: The study included 150 individuals with an age range of (35-55) years. Patients with diabetes for more than 5 years were excluded. Fifty healthy individuals constituted Group 1 (G1), fifty patients with T2DM constituted Group 2 (G2), and fifty T2DM patients with dyslipidemia constituted Group 3 (G3). Whole blood samples were drawn to measure HbA1c based on fluorescence immunoassay technology. The serum was separated to measure fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and high-density lipoproteins (HDL) by manual methods, while VCAM-1, and ICAM-1 were determined using the ELISA test. The study was conducted between November 2022 and April 2023 at the National Center for Diabetes Treatment and Research, Baghdad, Iraq. Results: Significantly higher levels of FSG and HbA1c were detected in G2 and G3 compared to G1, but non-significantly so when G3 was compared to G2. Significant higher levels of TG and TC levels were detected for G3 when compared to G1 and G2, but non-significantly so when G2 was compared to G1. HDL levels were significantly lower in G3 compared to G2 and G1, but non-significantly so when G2 was compared to G1. VCAM-1, and ICAM-1 were significantly higher in G2 compared to G1, and VCAM-1 level was significantly higher in G3 compared to G2. Non-significant differences in ICAM-1 levels were found between G3 and G2. Conclusion: VCAM-1 and ICAM-1 are potentially significant factors in the development of dyslipidemia in diabetes patients. They might serve as biomarkers to accurately predict the progression of cardiovascular disease.

The Role of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Predicting Complicated Appendicitis in Children.

Acute appendicitis is a common abdominal emergency observed in emergency departments (ED). Distinguishing between uncomplicated and complicated appendicitis is important in determining a treatment strategy. Serum soluble vascular cell adhesion molecule-1 (VCAM-1) is an inflammatory biomarker. We aimed to determine the role of VCAM-1 in predicting complicated appendicitis in children. Pediatric patients with suspected appendicitis admitted to the ED were enrolled in this prospective study. Pre-surgical serum VCAM-1 was tested in children with acute appendicitis within 72 h of symptoms (from day 1 to day 3). Serum VCAM-1 levels were further analyzed and compared between patients with and without complicated appendicitis. Among the 226 pediatric appendicitis patients, 70 had uncomplicated appendicitis, 138 had complicated appendicitis, and 18 had normal appendices. The mean serum VCAM-1 levels in patients with perforated appendicitis were higher than in those with simple appendicitis (p < 0.001). On day 1 to day 3, the mean VCAM-1 levels in patients with complicated appendicitis were all significantly higher than in those with uncomplicated appendicitis (all p < 0.001). Serum VCAM-1 levels may be helpful in differentiating uncomplicated and complicated appendicitis in children and could predict appendiceal perforation.

Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer's Disease.

Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.

Arterial stiffness and endothelial function in the long-term period after a coronavirus disease 2019

Aim. To assess endothelial function and arterial stiffness over time in patients after hospitalization with coronavirus disease 2019 (COVID-19) and compare them with a control group.Material and methods. A total of 53 patients over 18 years of age were hospitalized for COVID-19 in June — August 2021 was examined at two visits: the first — 10-16 months, the second — 14-23 months after discharge from the hospital. Control group included 53 patients from the ESSE-RF epidemiological study of a St. Petersburg population who did not have COVID-19, selected by sex, status of smoking, hypertension and type 2 diabetes. Endothelial function was assessed by the levels of vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) in plasma and the reactive hyperemia index (lnRHI) on the EndoPAT 2000 system. Carotid-femoral pulse wave velocity (cfPWV) was determined using the SphygmoCor device, while cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) — using the VaSera device.Results. The prevalence of endothelial vasomotor function disorders at the first and second visits in the active group did not differ significantly as follows: lnRHI £0,51 — 21% and 21%, cfPWV &gt;10 m/s — 17% and 14%, and SLSI &gt;9 — 28% and 34%, respectively. Plasma VCAM-1 levels were significantly higher during hospitalization than at the first and second visits — no differences were found between visits. The levels of lnRHI, vWF, cfPWV, CAVI, ABI at the first and second visits did not differ significantly. Post-COVID-19 patients differed from the control group only by a significantly higher ABI level at the second visit. According to the analysis of covariance, COVID-19 is associated with a CAVI increase at the first visit, as well as with an increase in ABI at both visits.Conclusion. The 1,5-2-year follow-up of patients after COVID-19, which required hospitalization, showed a decrease in the plasma endothelial dysfunction parameter VCAM-1. There is no changes in endothelial function and arterial stiffness over a period of time from 10-16 months to 14-23 months after hospitalization with COVID-19.

Abstract 2084: Endothelial Cells With Silenced Flrt2 Expression Exhibit Enhanced Retention On Vascular Graft Materials Under Fluid Shear Stress In Vitro

Myocardial infraction is a leading cause of death, and surgical intervention is often required to treat severe coronary artery disease. Autologous vessel grafts are the only option for bypass graft procedures. Synthetic vascular grafts less than 6 mm diameter fail due to unacceptable patency rates (~60% at 1 year). The loss of patency is accredited to platelet activation, thrombosis, and neointimal hyperplasia. A promising strategy to improve patency is to endothelialize synthetic vascular grafts ex-vivo, but previous attempts have met with modest success due to detachment of cells upon exposure to fluid shear stress. We previously used RNA-seq to characterized gene expression of endothelial cells (ECs) which remained adherent to synthetic grafts post shear stress. We found that fibronectin leucine-rich transmembrane protein 2 (FLRT2) was significantly downregulated in adherent subpopulations. We therefore hypothesize that suppressing FLRT2 expression in ECs will result in better retention on synthetic vascular grafts upon exposure to shear stress. We used silencing RNA approach using lipofectamine and confirmed successful knockdown of FLRT2 expression (Si-FLRT2). We then seeded Si-FLRT2 cells onto a commercially available Goretex graft material and subjected them to fluid shear stress of for 20 min. We then stained the samples with DAPI. We observed increased retention of Si-FLRT2 ECs on Goretex graft material in comparison to non-specifically targeted scramble siRNA containing ECs. In addition, we compared both vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) levels to assess endothelial cell activation and found that silencing of FLRT2 lead to decreased levels of both VCAM-1 (by 49.2%±3.5%) and ICAM-1 (by 57.1%±3.4%) suggestive of decreased endothelial cell activation. In conclusion, we show that FLRT2 plays an important role in adhesion of ECs onto a commercially available synthetic graft material and silencing its expression ex-vivo may have beneficial clinical outcomes. In addition, we found that FLRT2 silencing may lead to decreased endothelial cell activation and we would like to further investigate the molecular mechanisms underlying the role of FLRT2 in both EC adhesion and activation.

Association of endothelial dysfunction and peripheral arterial disease with sarcopenia in chronic kidney disease.

Endothelial dysfunction and peripheral arterial disease (PAD), which disturb skeletal muscle microperfusion, are highly prevalent in patients with chronic kidney disease (CKD). We evaluated the association of endothelial dysfunction and PAD with sarcopenia in patients with non-dialysis CKD. This cross-sectional study included 420 patients with stages 3-5 non-dialysis CKD aged 69.0±11.8years. Skeletal muscle index (skeletal muscle mass/height2), handgrip strength, 6-m gait speed and strength of hip flexion and knee extension were measured. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019. Endothelial dysfunction and PAD were assessed using the vascular reactivity index (VRI) and ankle-brachial index (ABI), respectively. A VRI<1.0 was classified as poor endothelial function, and an ABI<0.9 was defined as PAD. Additionally, endothelial and inflammatory biomarkers, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), asymmetric dimethylarginine, endothelin-1 (ET-1) and interleukin-6, were measured in a subgroup of 262 patients. Among the participants, 103 (24.5%) were classified as having sarcopenia. Compared with patients without sarcopenia, those with sarcopenia had significantly lower ABI (1.04±0.16 vs. 1.08±0.15, P=0.028 for the right ABI; 1.01±0.16 vs. 1.06±0.16, P=0.002 for the left ABI) and VRI (0.83±0.57 vs. 1.08±0.56, P<0.001) and had higher serum levels of ICAM-1 (P<0.001), VCAM-1 (P=0.003) and ET-1 (P=0.037). Multivariate logistic regression revealed that, beyond age and body mass index, the average ABI (odds ratio [OR]: 0.81/0.1 increase; 95% confidence interval [CI]: 0.67-0.98; P=0.032) and VRI (OR: 0.93/0.1 increase; 95% CI: 0.88-0.98; P=0.010) were independently associated with sarcopenia. Among the endothelial biomarkers measured, ICAM-1 (OR: 2.47/1-SD increase; 95% CI: 1.62-3.75) and VCAM-1 (OR: 1.91/1-SD increase; 95% CI: 1.27-2.87) were independent predictors of sarcopenia. Group stratification based on the cut-offs of VRI and ABI showed that those with both poor VRI and ABI had the greatest risk for sarcopenia (OR: 4.22; 95% CI: 1.69-10.49), compared with those with normal VRI and ABI. Endothelial dysfunction and PAD are independently associated with sarcopenia in patients with stages 3-5 CKD, suggesting the dominant role of vascular dysfunction in sarcopenia.

Blood Adhesion Molecules as Biomarkers in Children with Chronic Urticaria.

The prevailing etiological model of both acute and chronic urticaria implicates specific allergen exposure that triggers the local release of vasoactive factors and inflammatory adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), P-selectin and E-selectin in the superficial dermis. This study focused on the possible role of VCAM-1 and ICAM-1 as biomarkers in children with acute and chronic urticaria. This study involved 184 children, 40 with acute urticaria, 71 with chronic urticaria, and 73 matched comparison subjects. The serum levels of ICAM-1 and VCAM-1 were determined in venous blood in all the participants on enrollment. Antihistamine treatment was administered to all the patients. In the children with chronic urticaria, the Urticaria Activity Score Questionnaire (UAS7) was completed daily by the parents. In 16 of the patients with acute urticaria and 43 with chronic urticaria, the serum levels of ICAM-1 and VCAM-1 were determined at follow-up after 6-8 weeks of treatment. The mean serum levels of both VCAM-1 and ICAM-1 were higher in both groups of children with urticaria than in the comparison subjects at the start of the study. In the chronic urticaria group, the levels decreased significantly (p = 0.03 and p = 0.01, respectively) following treatment. Similarly, the acute urticaria group exhibited significant reduction in the mean levels of VCAM and ICAM (p < 0.001). In both groups, the mean level of ICAM after treatment was comparable with that of the comparison group. VCAM-1 and ICAM-1 are suggested as promising biomarkers for monitoring both acute and chronic urticaria in children. Future research should explore their utility in larger cohorts and investigate their role in personalized treatment strategies.

Serum Levels of Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1 as Biomarkers to Predict Radiotherapy Sensitivity in Cervical Cancer.

Cervical cancer is a significant global health burden, and individualized treatment approaches are necessary due to its heterogeneity. Radiotherapy is a common treatment modality; however, the response varies among patients. The identification of reliable biomarkers to predict radiotherapy sensitivity is crucial. A cohort of 189 patients with stage IB2-IVA cervical cancer, treated with radiotherapy alone or concurrent chemoradiotherapy, was included. Serum samples were collected before treatment, and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) concentrations were determined. Patients were categorized into radiotherapy-sensitive (RS) and radiotherapy-resistant (RR) groups based on treatment response. Clinicopathological characteristics and survival rates were analyzed. The analysis of clinicopathological characteristics showed that age, family history of cervical cancer and post-menopausal status did not significantly differ between RS and RR groups. Tumor size demonstrated a borderline significant association with radiotherapy response, while differentiation degree was significantly associated. Serum ICAM-1 and VCAM-1 concentrations were significantly higher in the RR group compared to the RS group. Combined detection of ICAM-1 and VCAM-1 improved the predictive ability for radiotherapy sensitivity. Higher serum ICAM-1 and VCAM-1 levels were observed in patients with lower tumor differentiation. Five-year overall survival rates differed significantly between patients with high and low ICAM-1 and VCAM-1 levels. Serum ICAM-1 and VCAM-1 levels show potential as predictive biomarkers for radiotherapy sensitivity in cervical cancer.

Endothelial cell-derived extracellular vesicles expressing surface VCAM1 promote sepsis-related acute lung injury by targeting and reprogramming monocytes.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life-threatening syndrome with no effective pharmacotherapy. Sepsis-related ARDS is the main type of ARDS and is more fatal than other types. Extracellular vesicles (EVs) are considered novel mediators in the development of inflammatory diseases. Our previous research suggested that endothelial cell-derived EVs (EC-EVs) play a crucial role in ALI/ARDS development, but the mechanism remains largely unknown. Here, we demonstrated that the number of circulating EC-EVs was increased in sepsis, exacerbating lung injury by targeting monocytes and reprogramming them towards proinflammatory macrophages. Bioinformatics analysis and further mechanistic studies revealed that vascular cell adhesion molecule 1 (VCAM1), overexpressed on EC-EVs during sepsis, activated the NF-κB pathway by interacting with integrin subunit alpha 4 (ITGA4) on the monocyte surface, rather than the tissue resident macrophage surface, thereby regulating monocyte differentiation. This effect could be attenuated by decreasing VCAM1 levels in EC-EVs or blocking ITGA4 on monocytes. Furthermore, the number of VCAM1+ EC-EVs was significantly increased in patients with sepsis-related ARDS. These findings not only shed light on a previously unidentified mechanism underling sepsis-related ALI/ARDS, but also provide potential novel targets and strategies for its precise treatment.

Cardiac Autonomic and Endothelial Function in Acute Lymphoblastic Leukaemia Patients Immediately After Chemotherapy and at the Three-Month Follow-up.

Acute lymphoblastic leukemia (ALL) is a malignant uncontrolled overproduction of immature lymphoid cells in blood and bone marrow. The primary treatment of ALL is chemotherapy. Chemotherapy can have myriad systemic side effects, notably cardiovascular derangement. Autonomic derangement occurrence in cancer patients signifies cardiovascular risk in them and is a determinant of cardiovascular morbidity and mortality. Elevated soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) levels implicated in the regulation of inflammation indicate endothelial dysfunction. High levels of high-sensitivity C-reactive protein (hsCRP) can be indicative of low-grade inflammation. Hence, in this study the cardiac autonomic function and endothelial and inflammatory biomarker levels in adult patients with ALLwere assessed immediately and three months after chemotherapy. In this longitudinal study, 30 ALL patients (23 males, seven females) aged between 18 to 50 years, who had completed chemotherapy regimens, and 30 age and gender-matched healthy participants (controls) were recruited. Cardiac autonomic function tests (short-term heart rate variability (HRV), 30:15 ratio, synaptic excitation and inhibition (E/I) ratio, diastolic blood pressure (DBP) response to isometric hand grip), endothelial markers (sVCAM-1 and sICAM-1), and inflammatory marker (hsCRP) were assessed immediately and at three months after chemotherapy. Magnitudes of time domain and frequency domain indices, conventional autonomic function test indices, and biomarkers were deranged in ALL patients immediately after chemotherapy. After three months, cardiac autonomic function parameters were found to improve in the form of increased root mean square of successive differences between normal heartbeats (RMSSD), standard deviation of the interbeat intervals of normal sinus beats (SDNN), total power, high-frequency (HF)nu, and decreased low-frequency(LF)nu & LF-HF ratio. Endothelial (sVCAM-1) and inflammatory markers (hsCRP) were lower in the patient group as compared to the controls immediately after chemotherapy. Three months after chemotherapy, the levels of endothelial and inflammatory markers did not show much change. In this study, we found ALL patients showed higher sympathetic drive, decreased parasympathetic modulation, and sympathovagal imbalance immediately after chemotherapy as compared to the controls, indicating cardiovascular risk. After three months, improvement in cardiovascular autonomic function was observed. ALL itself is a state of inflammation with elevated endothelial and inflammatory markers; thus, the decreased endothelial and inflammatory markers could be attributed to the immediate effect of chemotherapy.