Vascular Endothelial Glycocalyx Research Articles

Relationship between fat embolism and endothelial glycocalyx

Fat embolism (FE) is acknowledged as one of the significant causes of sudden death following traumatic injury. To clarify the relevance of vascular endothelial glycocalyx (EGC) damage and FE, temporal changes in the mRNA levels of inflammatory cytokines associated with EGC components were investigated in an experimental fat embolization rat model. Nine-week-old rats were used as FE models through triolein injection (TO) and femoral fracture (FX), and physiological saline was administered to the control group. RT-qPCR and fat staining were performed. The target genes were Il6, Il10, Tnf, Elane, Sdc1, Sdcbp, Vcan, Hyal1, Fn1, and CD14. Notably, FE was detected in 100% and 5.6% of the TO and FX groups, respectively, using fat staining. Bimodal peaks in the mRNA expression levels of Sdc1, Tnf, Elane, IL6, and IL10 were observed 4 and 20 h after treatment in both groups. In the TO group, mRNA expression peaked at 4 h and then declined to the lowest level at 16 h. The incidence of fat emboli due to trauma was consistent with that reported in previous studies. Bimodal mRNA peaks may correspond to FE progression, in which physical obstructions are followed by biochemical reactions. The fluctuation in Sdc1 expression suggests that the initial peak resulted from physical EGC damage. The subsequent peak could be because of EGC damage caused by the secretion of inflammatory cytokines induced by oleic acid from lipid droplet decomposition. These results suggest that EGC disorders caused by lipid droplets may induce lung damage during FE.

Trauma promotes heparan sulfate modifications and cleavage that disrupt homeostatic gene expression in microvascular endothelial cells.

Introduction: Heparan sulfate (HS) in the vascular endothelial glycocalyx (eGC) is a critical regulator of blood vessel homeostasis. Trauma results in HS shedding from the eGC, but the impact of trauma on HS structural modifications that could influence mechanisms of vascular injury and repair has not been evaluated. Moreover, the effect of eGC HS shedding on endothelial cell (EC) homeostasis has not been fully elucidated. The objectives of this work were to characterize the impact of trauma on HS sulfation and determine the effect of eGC HS shedding on the transcriptional landscape of vascular ECs. Methods: Plasma was collected from 25 controls and 49 adults admitted to a level 1 trauma center at arrival and 24h after hospitalization. Total levels of HS and angiopoietin-2, a marker of pathologic EC activation, were measured at each time point. Enzymatic activity of heparanase, the enzyme responsible for HS shedding, was determined in plasma from hospital arrival. Liquid chromatography-tandem mass spectrometry was used to characterize HS di-/tetrasaccharides in plasma. In vitro work was performed using flow conditioned primary human lung microvascular ECs treated with vehicle or heparinase III to simulate human heparanase activity. Bulk RNA sequencing was performed to determine differentially expressed gene-enriched pathways following heparinase III treatment. Results: We found that heparanase activity was increased in trauma plasma relative to controls, and HS levels at arrival were elevated in a manner proportional to injury severity. Di-/tetrasaccharide analysis revealed lower levels of 3-O-sulfated tetramers with a concomitant increase in ΔIIIS and ΔIIS disaccharides following trauma. Admission levels of total HS and specific HS sulfation motifs correlated with 24-h angiopoietin-2 levels, suggesting an association between HS shedding and persistent, pathological EC activation. In vitro pathway analysis demonstrated downregulation of genes that support cell junction integrity, EC polarity, and EC senescence while upregulating genes that promote cell differentiation and proliferation following HS shedding. Discussion: Taken together, our findings suggest that HS cleavage associated with eGC injury may disrupt homeostatic EC signaling and influence biosynthetic mechanisms governing eGC repair. These results require validation in larger, multicenter trauma populations coupled with in vivo EC-targeted transcriptomic and proteomic analyses.

Mechanisms of triple‐negative breast cancer extravasation: Impact of the physical environment and endothelial glycocalyx

AbstractCancer metastasis is the leading cause of death for those afflicted with cancer. In cancer metastasis, the cancer cells break off from the primary tumor, penetrate nearby blood vessels, and attach and extravasate out of the vessels to form secondary tumors at distant organs. This makes extravasation a critical step of the metastatic cascade. Herein, with a focus on triple‐negative breast cancer, the role that the prospective secondary tumor microenvironment's mechanical properties play in circulating tumor cells' extravasation is reviewed. Specifically, the effects of the physically regulated vascular endothelial glycocalyx barrier element, vascular flow factors, and subendothelial extracellular matrix mechanical properties on cancer cell extravasation are examined. The ultimate goal of this review is to clarify the physical mechanisms that drive triple‐negative breast cancer extravasation, as these mechanisms may be potential new targets for anti‐metastasis therapy.

HYDROGEN-RICH SALINE UPREGULATES THE SIRT1/NF-ΚB SIGNALING PATHWAY AND REDUCES VASCULAR ENDOTHELIAL GLYCOCALYX SHEDDING IN SEPSIS-INDUCED ACUTE KIDNEY INJURY.

Sepsis causes dysfunction in different organs, but the pathophysiological mechanisms behind it are similar and mainly involve complex hemodynamic and cellular dysfunction. The importance of microcirculatory dysfunction in sepsis is becoming increasingly evident, in which endothelial dysfunction and glycocalyx degradation play a major role. This study aimed to investigate the effects of hydrogen-rich saline (HRS) on renal microcirculation in septic renal failure, and whether Sirt1 was involved in the renoprotective effects of HRS. Rats model of sepsis was established by cecal ligation and puncture, and septic rats were intraperitoneal injected with HRS (10 mL/kg). We found that in sepsis, the degree of glycocalyx shedding was directly proportional to the severity of sepsis. The seven-day survival rate of rats in the HRS+CLP group (70%) was higher than that of the CLP group (30%). HRS improved acidosis and renal function and reduced the release of inflammatory factors (TNF, IL-1β, and IL-6). The endothelial glycocalyx of capillaries in the HRS+CLP group (115 nm) was observed to be significantly thicker than that in the CLP group (44 nm) and EX527 (67.2 nm) groups by electron microscopy, and fewer glycocalyx metabolites (SDC-1, HS, HA, and MMP9) were found in the blood. Compared with the CLP group, HRS reduced renal apoptosis and upregulated Sirt1 expression, and inhibited the NF-κB/MMP9 signaling pathway. In addition, HRS did not damage immune function in septic rats as well. Generally speaking, our results suggest that HRS can alleviate the inflammatory response, inhibit glycocalyx shedding, improve septic kidney injury, and enhance survival rate.

Spleen derived monocytes regulate pulmonary vascular permeability in Hepatopulmonary syndrome through the OSM-FGF/FGFR1 signaling

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.

Destruction of vascular endothelial glycocalyx during formation of pre-metastatic niches

A special microenvironment called the “pre-metastatic niche” is thought to help primary tumor cells migrate to new tissues and invade them, in part because the normal barrier function of the vascular endothelium is compromised. While the primary tumor itself can promote the creation of such niches by secreting pro-metastatic factors, the underlying molecular mechanisms are still poorly understood. Here, we show that the injection of primary tumor-secreted pro-metastatic factors from B16F10 melanoma or 4T1 breast cancer cells into healthy mice can induce the destruction of the vascular endothelial glycocalyx, which is a polysaccharide coating on the vascular endothelial lumen that normally inhibits tumor cell passage into and out of the circulation. However, when human umbilical vein endothelial cultures were treated in vitro with these secreted pro-metastatic factors, no significant destruction of the glycocalyx was observed, implying that this destruction requires a complex in vivo microenvironment. The tissue section analysis revealed that secreted pro-metastatic factors could clearly upregulate macrophage-related molecules such as CD11b and tumor necrosis factor-α (TNF-α) in the heart, liver, spleen, lung, and kidney, which is associated with the upregulation and activation of heparanase. In addition, macrophage depletion significantly attenuated the degradation of the vascular endothelial glycocalyx induced by secreted pro-metastatic factors. This indicates that the secreted pro-metastatic factors that destroy the vascular endothelial glycocalyx rely primarily on macrophages. Our findings suggest that the formation of pre-metastatic niches involves degradation of the vascular endothelial glycocalyx, which may hence be a useful target for developing therapies to inhibit cancer metastasis.

Erythrocyte glycocalyx sensitivity to sodium is associated with salt sensitivity of blood pressure in women but not men.

While salt sensitivity of blood pressure (SSBP) is a risk factor for hypertension, end-organ damage and death, most studies are conducted in western countries and in White people. We previously found that the prevalence of SSBP in Blacks living in Sub-Saharan Africa is as high as 75-80% like what has been reported in the west. Erythrocyte glycocalyx sensitivity to sodium (eGCSS), a marker of sodium-induced damage to the erythrocyte and vascular endothelial glycocalyx is thought to be related to blood pressure perturbations associated with salt intake. We hypothesized that SSBP correlates with eGCSS differently in men and women in Black people. We conducted a cross sectional study using data from our recent clinical trial from Livingstone University Teaching Hospital among 117 normotensive young adults. We used a "salt blood test" to determine eGCSS and an immediate pressor response to oral salt (IPROS) for the diagnosis of SSBP. The proportion of males were equal to females and the median age (interquartile range) of the participants was 29 (22-45) years. The eGCSS scores were higher in salt-resistant females compared to salt-sensitive females and males. eGCSS correlated negatively with SSBP (AOR 0.98, 95% CI 0.97-0.99, p = 0.008), however, this relationship was driven by female sex and abrogated by male sex. Although blood pressure elevations exhibited a sustained bimodal pattern in both sexes, in males, systolic and diastolic blood pressure never returned to baseline during the time course as it did in females. In this study, eGCSS correlated negatively with SSBP in black women but not in black men and the pressor response to dietary salt was significantly higher in men compared to women. These results suggest that women tend to have a higher disruption of the vascular endothelial glycocalyx by an acute salt load, implying that acute changes in blood pressure may not be driven directly by the endothelial glycocalyx. Our findings suggest a novel mechanism linking eGCSS and SSBP with potential implications for sex differences in salt-induced cardiovascular disease.Clinical trial registration: https://clinicaltrials.gov/, identifier [NCT04844255].

Recombinant antithrombin attenuates acute kidney injury associated with rhabdomyolysis: an in vivo animal study

BackgroundRhabdomyolysis is characterized by the destruction and necrosis of skeletal muscle tissue, resulting in acute kidney injury (AKI). Recombinant antithrombin (rAT) has DNA repair and vascular endothelial-protection properties. Herein, we investigated whether rAT therapy has beneficial effects against rhabdomyolysis-induced AKI. Ten-week-old male B6 mice were injected with 5 mL/kg of 50% glycerol intramuscularly in the left thigh after 24 h of fasting to create a rhabdomyolysis mouse model. Further, 750 IU/kg rAT was injected intraperitoneally at 24 and 72 h after the rhabdomyolysis model was established. The mice were euthanized after 96 h for histological analysis. Saline was administered to mice in the control group.ResultsBlood tests show elevated serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin levels in rhabdomyolysis. Loss of tubular epithelial cell nuclei and destruction of the tubular luminal surface structure was observed in the untreated group, which improved with rAT treatment. Immunostaining for Ki-67 showed increased Ki-67-positive nuclei in the tubular epithelial cells in the rAT group, suggesting that rAT may promote tubular epithelial cell regeneration. The microvilli of the brush border of the renal tubules were shed during rhabdomyolysis, and rAT treatment reduced this injury. The vascular endothelial glycocalyx, which is usually impaired by rhabdomyolysis, became functional following rAT treatment.ConclusionsTreatment with rAT suppressed rhabdomyolysis-induced AKI, suggesting that rAT therapy may be a novel therapeutic approach.

Vascular endothelial glycocalyx shedding in ventilator-induced lung injury in rats

Endothelial permeability deterioration is involved in ventilator-induced lung injury (VILI). The integrality of vascular endothelial glycocalyx (EG) is closely associated with endothelial permeability. The hypothesis was that vascular EG shedding participates in VILI through promoting endothelial permeability. In the present study, male Sprague-Dawley (SD) rats were ventilated with high tidal volume (VT =40 ml/kg) or low tidal volume (VT =8 ml/kg) to investigate the effects of different tidal volume and ventilation durations on EG in vivo. We report disruption of EG during the period of high tidal volume ventilation characterized by increased glycocalyx structural components (such as syndecan-1, heparan sulfate, hyaluronan) in the plasma and decreased the expression of syndecan-1 in the lung tissues. Mechanistically, the disruption of EG was associated with increased proinflammatory cytokines and matrix metalloproteinase in the lung tissues. Collectively, these results demonstrate that the degradation of EG is involved in the occurrence and development of VILI in rats, and the inflammatory mechanism mediated by activation of the NF-κB signaling pathway may be partly responsible for the degradation of EG in VILI in rats. This study enhances our understanding of the pathophysiological processes underlying VILI, shedding light on potential therapeutic targets to mitigate VILI.

The association between prolonged capillary refill time and microcirculation changes in children with sepsis

BackgroundsIn children with sepsis, circulatory shock and multi-organ failure remain major contributors to mortality. Prolonged capillary refill time (PCRT) is a clinical tool associated with disease severity and tissue hypoperfusion. Microcirculation assessment with videomicroscopy represents a promising candidate for assessing and improving hemodynamic management strategies in children with sepsis. Particularly when there is loss of coherence between the macro and microcirculation (hemodynamic incoherence). We sought to evaluate the association between PCRT and microcirculation changes in sepsis.MethodsThis was a prospective cohort study in children hospitalized with sepsis. Microcirculation was measured using sublingual video microscopy (capillary density and flow and perfused boundary region [PBR]—a parameter inversely proportional to vascular endothelial glycocalyx thickness), phalangeal tissue perfusion, and endothelial activation and glycocalyx injury biomarkers. The primary outcome was the association between PCRT and microcirculation changes.ResultsA total of 132 children with sepsis were included, with a median age of two years (IQR 0.6–12.2). PCRT was associated with increased glycocalyx degradation (PBR 2.21 vs. 2.08 microns; aOR 2.65, 95% CI 1.09–6.34; p = 0.02) and fewer 4–6 micron capillaries recruited (p = 0.03), with no changes in the percentage of capillary blood volume (p = 0.13). Patients with hemodynamic incoherence had more PBR abnormalities (78.4% vs. 60.8%; aOR 2.58, 95% CI 1.06–6.29; p = 0.03) and the persistence of these abnormalities after six hours was associated with higher mortality (16.5% vs. 6.1%; p < 0.01). Children with an elevated arterio-venous CO2 difference (DCO2) had an abnormal PBR (aOR 1.13, 95% CI 1.01–1.26; p = 0.03) and a lower density of small capillaries (p < 0.05). Prolonged capillary refill time predicted an abnormal PBR (AUROC 0.81, 95% CI 0.64–0.98; p = 0.03) and relative percentage of blood in the capillaries (AUROC 0.82, 95% CI 0.58–1.00; p = 0.03) on admission. A normal CRT at 24 h predicted a shorter hospital stay (aOR 0.96, 95% CI 0.94–0.99; p < 0.05).ConclusionsWe found an association between PCRT and microcirculation changes in children with sepsis. These patients had fewer small capillaries recruited and more endothelial glycocalyx degradation. This leads to nonperfused capillaries, affecting oxygen delivery to the tissues. These disorders were associated with hemodynamic incoherence and worse clinical outcomes when the CRT continued to be abnormal 24 h after admission.

Syndecan-1 as a predictor of vulnerable atherosclerotic plaques.

Cardiovascular disease remains a major global health concern, with atherosclerosis (AS) being a significant contributor. Vulnerable plaques play a critical role in acute cardiovascular events. Syndecan-1 (SDC-1), a vital membrane proteoglycan in the vascular endothelial glycocalyx, is believed to be associated with plaque progression. However, its precise relationship with severity and vulnerability of atherosclerotic plaque remains unclear. This study aimed to investigate SDC-1 expression and its potential correlation with plaque vulnerability in ApoE-/- atherosclerosis mouse model. Eight-week-old mice were induced into the AS model using a high-fat diet (HFD) and/or partial ligation of the left common carotid artery (PLCA), with a chow diet (CD) control group. After 16weeks, plaques in the aortic root showed the following order: HFD + PLCA group > HFD group > CD + PLCA group > CD group. Immunohistochemistry revealed heightened accumulation of lipid/foam cells and CD68-labeled macrophages in the plaques, elevated vascular endothelial growth factor (VEGF), and matrix Metalloproteinase-9 (MMP-9) in the HFD + PLCA group's plaques, along with reduced collagen and α-SMA-labeled smooth muscle cells, resulting in the highest vulnerability index value. Immunohistofluorescence analysis of frozen plaque sections showed significantly higher SDC-1 expression in the AS mice group compared to the CD group, both positively correlated with plaque vulnerability. Serum analysis demonstrated elevated levels of SDC1, sphingosine 1-phosphate (S1P), and VEGF-A in the AS mice, all positively correlated with plaque vulnerability. Multivariate analysis identified SDC1 as an independent predictor of plaque vulnerability. This study enhances our understanding of plaque vulnerability mechanisms and presents SDC1 as a potential biomarker for atherosclerosis. These findings underscore the importance of addressing modifiable risk factors, such as diet and hemodynamics and suggest the utility of serum SDC1 as a valuable clinical marker. Ultimately, these insights may lead to more effective strategies in combating cardiovascular diseases and improving patient outcomes.

Soluble vascular endothelial glycocalyx proteoglycans as potential therapeutic targets in inflammatory diseases.

Reducing the activity of cytokines and leukocyte extravasation is an emerging therapeutic strategy to limit tissue-damaging inflammatory responses and restore immune homeostasis in inflammatory diseases. Proteoglycans embedded in the vascular endothelial glycocalyx, which regulate the activity of cytokines to restrict the inflammatory response in physiological conditions, are proteolytically cleaved in inflammatory diseases. Here we critically review the potential of proteolytically shed, soluble vascular endothelial glycocalyx proteoglycans to modulate pathological inflammatory responses. Soluble forms of the proteoglycans syndecan-1, syndecan-3 and biglycan exert beneficial anti-inflammatory effects by the removal of chemokines, suppression of proinflammatory cytokine expression and leukocyte migration, and induction of autophagy of proinflammatory M1 macrophages. By contrast, soluble versikine and decorin enhance proinflammatory responses by increasing inflammatory cytokine synthesis and leukocyte migration. Endogenous syndecan-2 and mimecan exert proinflammatory effects, syndecan-4 and perlecan mediate beneficial anti-inflammatory effects and glypican regulates Hh and Wnt signaling pathways involved in systemic inflammatory responses. Taken together, targeting the vascular endothelial glycocalyx-derived, soluble syndecan-1, syndecan-2, syndecan-3, syndecan-4, biglycan, versikine, mimecan, perlecan, glypican and decorin might be a potential therapeutic strategy to suppress overstimulated cytokine and leukocyte responses in inflammatory diseases.

Investigation of the relationship between intradialytic hypotension during hemodialysis and serum syndecan-1 concentration

Intradialytic hypotension and arrhythmias are complications of hemodialysis. They are associated with decreased intravascular volume due to reduced ultrafiltration volume, cardiac function, and arterial tone. The vascular endothelial glycocalyx, which exists on the surface of healthy vascular endothelial cells and maintains vascular permeability, has been suggested to be impaired by hemodialysis. This single-center retrospective study evaluated the association between syndecan-1, an endothelial glycocalyx dysfunction marker, and complications of hemodialysis. We enrolled 92 patients who underwent outpatient hemodialysis at Gifu Seiryu Hospital from April to July 2022 (346 hemodialysis sessions). The median duration and time of hemodialysis were 40 months and 4.1 h, respectively. Median serum syndecan-1 levels were 67.7 ng/mL before and 98.3 ng/mL after hemodialysis. Hemodialysis complications were noted in 68 sessions, all of which were hypotension. No correlation between pre-hemodialysis syndecan-1 levels and the incidence of complications was observed. However, a positive correlation between the amount of change in syndecan-1 levels before and after hemodialysis and the incidence of hemodialysis complications was noted. Conversely, syndecan-1 levels did not correlate with brain or atrial natriuretic peptides, suggesting that impairment of the vascular endothelial glycocalyx may be a possible cause of intradialytic hypotension and may be useful in preventing intradialytic hypotension.

The impact of vascular endothelial glycocalyx on the pathogenesis and treatment of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a complex disorder characterized by widespread activation of blood clotting mechanisms throughout the body. Understanding the role of vascular endothelial glycocalyx in the pathogenesis and treatment of DIC is crucial for advancing our knowledge in this field. The vascular endothelial glycocalyx is a gel-like layer that coats the inner surface of blood vessels. It plays a significant role in maintaining vascular integrity, regulating fluid balance, and preventing excessive clotting. In the pathogenesis of DIC, the disruption of the vascular endothelial glycocalyx is a key factor. Pathological conditions trigger the activation of enzymes, including heparanase, hyaluronase, and matrix metalloproteinase. This activation leads to glycocalyx degradation, subsequently exposing endothelial cells to procoagulant stimuli. Additionally, the ANGPTs/Tie-2 signaling pathway plays a role in the imbalance between the synthesis and degradation of VEG, exacerbating endothelial dysfunction and DIC. Understanding the mechanisms behind glycocalyx degradation and its impact on DIC can provide valuable insights for the development of targeted therapies. Preservation of the glycocalyx integrity may help prevent the initiation and propagation of DIC. Strategies such as administration of exogenous glycocalyx components, anticoagulant agents, or Tie-2 antibody agents have shown promising results in experimental models. In conclusion, the vascular endothelial glycocalyx plays a crucial role in the pathogenesis and treatment of DIC. Further research in this field is warranted to unravel the complex interactions between the glycocalyx and DIC, ultimately leading to the development of novel therapies.

Acute respiratory distress syndrome, acute kidney injury, and mortality after trauma are associated with increased circulation of syndecan-1, soluble thrombomodulin, and receptor for advanced glycation end products.

Disruption of the vascular endothelium and endothelial glycocalyx (EG) has been described after severe trauma. Plasma has been suggested to restore microvascular integrity by preservation and repair of the EG. We sought to evaluate whether plasma administered in a 1:1:1 ratio was associated with less endothelial marker circulation than a 1:1:2 ratio. This is a secondary analysis of the PROPPR trial, which investigated post-traumatic resuscitation with platelets, plasma, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Syndecan-1, soluble thrombomodulin (sTM), and receptor for advanced glycation end products (RAGE) were quantified for each treatment group on admission and at 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. Patients were excluded if they did not survive longer than 3 hours or had data from fewer than two time points. Three hundred eight patients in the 1:1:1 group and 291 in the 1:1:2 group were analyzed. There were no statistically significant differences in syndecan-1, sTM, or RAGE between treatment groups at any time point ( p > 0.05). Patients who developed acute respiratory distress syndrome, acute kidney injury, and death had significantly elevated biomarker expression at most time points when compared with patients who did not develop these sequelae ( p < 0.05). Administration of FFP in a 1:1:1 ratio does not consistently affect circulation of endothelial biomarkers following significant trauma when compared with a 1:1:2 ratio. The development of post-traumatic ARDS, AKI, and death was associated with increased endothelial biomarker circulation. Therapeutic/Care Management; Level III.

The role of anesthetic drug and technique in endothelial glycocalyx: A narrative review.

The level of endothelial glycocalyx (EG) shedding is associated with morbidity and mortality, and vascular endothelial barrier dysfunction is one of the pivotal clinical problems faced by critically ill patients, so research on the protective effects of EG is of great clinical significance for the treatment of critically ill diseases. Studies have illustrated that clinical anesthesia has different degrees of effects on vascular EG. Therefore, we reviewed the effects of distinct anesthesia methods and diverse anesthetic drugs on EG, aiming to provide a brief summary of what we know now, and to discuss possible future directions for investigations in this area. So as to provide a theoretical basis for future research on potential EG-positive drugs and targets, to minimize perioperative complications and improve the prognosis of surgical patients.

Identification of MEST as a critical player in mechanotransduction of endothelial cells in response to shear stress in atherosclerosis

OBJECTIVE: Atherosclerosis (AS) is a chronic disease characterized by the inflammation and the deposition of cholesterol in arterial intima, which is the common pathological basis of various cardiovascular and cerebrovascular diseases. Fluid shear stress (FSS) is an important regulatory factor of cellular cholesterol metabolism during the occurrence and progression of AS. However, the mechanism by which FSS regulated the deposition of cholesterol in AS remains unclear. METHODS: By using a novel cell model of foaming established by piled vascular endothelial cells, the transcriptome sequencing and the bioinformatics data mining were carried out to screen the key differential genes involved in the foaming of vascular endothelial cells and the FSS mechanotransduction, and then the qRT-PCR validation of them was performed. Also, the levels of the identified molecules in ApoE-/- atherosclerotic mice were detected. Finally, the role of MEST in vascular endothelial cells was explored by BODIPY staining upon MEST knockdown. RESULTS: We identified MEST that regulated by FSS is downregulated in foaming endothelial cells, and is also reduced in the atherosclerotic lesions. MEST might be closely associated with lipid metabolism, vascular endothelial glycocalyx, G protein-coupled receptor signaling, and cell-to-cell communication. Knockdown of MEST induced lipid accumulation in vascular endothelial cells. CONCLUSION: MEST is an antiatherogenic molecule, which might control the endothelial injury and atherogenic initiation. This project was supported by the National Natural Science Foundation of China (12272246). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Targeting immune cell trafficking and vascular endothelial cells in psoriasis.

The role of the vasculature in inflammatory skin disorders is an exciting area of investigation. Vascular endothelial cells (ECs) play instrumental roles in maintaining the vascular barrier and control of blood flow. Furthermore, ECs contribute to a variety of immune responses, such as targeting immune cells to specific areas of vascular damage, infection, or foreign material. However, mechanisms through which ECs participate in immune-mediated responses remain to be fully explored. In this issue of the JCI, Li, Shao, et al. report on vascular endothelial glycocalyx destruction and the mechanisms through which EC dysfunction contributes to the well-characterized immune-mediated features of psoriasis, a chronic inflammatory skin disease. Here, we discuss the implications of these findings and highlight some risks and benefits of existing therapies designed to target immune cell trafficking in a variety of inflammatory conditions.

PULMONARY VASCULAR ENDOTHELIAL GLYCOCALYX DEGRADATION CONTRIBUTES TO ACUTE LUNG INJURY IN EXPERIENCING HEATSTROKE.

Objectives: This study investigated the role and potential involvement of pulmonary vascular glycocalyx degradation in acute lung injury in rats with severe heatstroke (HS). Methods: Rats in an established HS model were exposed to a heated environment for 60 min in an incubator (temperature, 40°C ± 2°C; humidity, 65% ± 5%). Following pretreatment with heparanase III (HPSE III) or heparin, pathological lung injury, arterial blood gas, alveolar barrier disruption, and hemodynamic changes were evaluated. The vascular endothelial structures of the lungs were examined using electron microscopy. The concentration of Evans blue dye in the lungs and arterial blood gas were assessed. An enzyme-linked immunosorbent assay was used to quantify the plasma concentration of heparan sulfate proteoglycan. The expression of glypican-1 and syndecan-1 in pulmonary vessels was measured using immunofluorescence. Western blots were used to detect the expression of TNF-α, IL-6, and vascular endothelial biomarkers in the rat lungs. Pulmonary apoptosis was assessed using a TUNEL (terminal dUTP nick end labeling) assay, and the concentrations of malondialdehyde were measured. Results: Glycocalyx shedding aggravated lung injuries. Severe histopathological damage was observed, and indexes of lung function deviated from abnormal ranges. In addition, pulmonary vascular endothelial cells were disrupted. Compared with the HS group, the plasma concentration of heparan sulfate proteoglycan significantly increased in the HPSE group ( P < 0.05). The expression of glypican-1 and syndecan-1 decreased, and the extravasation of Evans blue dye increased ( P < 0.01). Endothelial biomarker expression increased in the lung tissue, whereas occludin expression decreased. Moreover, TNF-α and IL-6 were overexpressed following heat stress. Furthermore, apoptosis of pulmonary tissues and the concentration of malondialdehyde in rat lungs increased in the HS and HPSE groups. Conclusions : Heatstroke induced pulmonary glycocalyx degradation, which increased vascular permeability and aggravated vascular endothelial dysfunction, contributing to apoptosis, inflammation, and oxidation in the pulmonary tissues.

Preservation of vascular endothelial glycocalyx and barrier by activation of adenosine A2A receptor (A2AR) improved renal dysfunction in cirrhotic rats

Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 [bile duct ligated (BDL)+PSB0777] treatment.Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier [VE-cadherin (CDH5) and β-catenin (CTNNB1)]/glycocalyx [syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2)] markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats [BMDM-CM (BDL)] induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction.