RESUMO
Neurogenic pulmonary edema secondary to acute brain injury (ABI) is a common and fatal disease condition. However, the pathophysiology of brain-lung interactions is incompletely understood. This study aims to investigate whether sympathetic activation-mediated high fluid shear stress after ABI would damage pulmonary endothelial glycocalyx thus leading to increased pulmonary capillary permeability. The tricuspid annular plane systolic excursion (TAPSE) was detected in a rat model of controlled cortical impact (CCI) and CCI + transection of the cervical sympathetic trunk (TCST). Changes in pulmonary capillary permeability were assessed by analyzing the Evans blue, measuring the dry/wet weight ratio of the lungs and altering protein levels in the bronchoalveolar lavage fluid (BALF). The parallel-plate flow chamber system was used to simulate the fluid shear stress in vitro. Western blotting and immunofluorescence staining were used to determine the expression levels of hyaluronan-binding protein (CEMIP), syndecan-1 and tight junction proteins (TJPs, including claudin-5 and occludin). TCST could restrain cardiac overdrive and sympathetic activation in a rat model of CCI. Compared to the CCI group, the CCI + TCST group showed a reduction of CEMPI (which degrades hyaluronic acid), along with an increase of syndecan-1 and TJPs. CCI + TCST group presented decreasing pulmonary capillary permeability. In vitro, high shear stress (HSS) increased the expression of CEMIP and reduced syndecan-1 and TJPs, which was coordinated with the results in vivo. Our findings show that sympathetic activation-mediated high fluid shear stress after ABI would damage pulmonary endothelial glycocalyx thus leading to increased pulmonary capillary permeability.
Assuntos
Lesões Encefálicas , Sindecana-1 , Ratos , Animais , Sindecana-1/metabolismo , Glicocálix/metabolismo , Permeabilidade Capilar , Pulmão/metabolismo , Lesões Encefálicas/metabolismoRESUMO
Intermittent fasting has become of interest for its possible metabolic benefits and reduction of inflammation and oxidative damage, all of which play a role in the pathophysiology of diabetic nephropathy. We tested in a streptozotocin (60 mg/kg)-induced diabetic apolipoprotein E knockout mouse model whether repeated fasting mimicking diet (FMD) prevents glomerular damage. Diabetic mice received 5 FMD cycles in 10 wk, and during cycles 1 and 5 caloric measurements were performed. After 10 wk, glomerular endothelial morphology was determined together with albuminuria, urinary heparanase-1 activity, and spatial mass spectrometry imaging to identify specific glomerular metabolic dysregulation. During FMD cycles, blood glucose levels dropped while a temporal metabolic switch was observed to increase fatty acid oxidation. Overall body weight at the end of the study was reduced together with albuminuria, although urine production was dramatically increased without affecting urinary heparanase-1 activity. Weight loss was found to be due to lean mass and water, not fat mass. Although capillary loop morphology and endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced together with the presence of UDP-glucuronic acid. Mass spectrometry imaging further revealed reduced protein catabolic breakdown products and increased oxidative stress, not different from diabetic mice. In conclusion, although FMD preserves partially glomerular endothelial glycocalyx, loss of lean mass and increased glomerular oxidative stress argue whether such diet regimes are safe in patients with diabetes.NEW & NOTEWORTHY Repeated fasting mimicking diet (FMD) partially prevents glomerular damage in a diabetic mouse model; however, although endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced in the presence of UDP-glucuronic acid. The weight loss observed was of lean mass, not fat mass, and increased glomerular oxidative stress argue whether such a diet is safe in patients with diabetes.
Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Jejum , Glicocálix , Glomérulos Renais , Estresse Oxidativo , Animais , Glicocálix/metabolismo , Glicocálix/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Glicemia/metabolismo , Albuminúria/metabolismo , Camundongos , Glucuronidase/metabolismo , Camundongos Knockout para ApoE , Camundongos Endogâmicos C57BL , DietaRESUMO
The endothelial glycocalyx (EGC) is a layer of proteoglycans (associated with glycosaminoglycans) and glycoproteins, which adsorbs plasma proteins on the luminal surface of endothelial cells. Its main function is to participate in separating the circulating blood from the inner layers of the vessels and the surrounding tissues. Physiologically, the EGC stimulates mechanotransduction, the endothelial charge, thrombocyte adhesion, leukocyte tissue recruitment, and molecule extravasation. Hence, severe impairment of the EGC has been implicated in various pathological conditions, including sepsis, diabetes, chronic kidney disease, inflammatory disorders, hypernatremia, hypervolemia, atherosclerosis, and ischemia/reperfusion injury. Moreover, alterations in EGC have been associated with altered responses to therapeutic interventions in conditions such as cardiovascular diseases. Investigation into the function of the glycocalyx has expanded knowledge about vascular disorders and indicated the need to consider new approaches in the treatment of severe endothelial dysfunction. This review aims to present the current understanding of the molecular mechanisms underlying cardiovascular diseases and to elucidate the impact of heart surgery on EGC dysfunction.
RESUMO
Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81-0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.
Assuntos
COVID-19 , Glicocálix , Interleucina-6 , Sepse , Humanos , COVID-19/patologia , COVID-19/metabolismo , COVID-19/complicações , Glicocálix/metabolismo , Glicocálix/patologia , Interleucina-6/metabolismo , Interleucina-6/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Sepse/patologia , Sepse/metabolismo , Sepse/complicações , Idoso , Estudos Prospectivos , SARS-CoV-2/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Anticorpos Monoclonais HumanizadosRESUMO
Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.
Assuntos
Glicocálix , Doenças do Sistema Nervoso Periférico , Humanos , Camundongos , Animais , Vincristina/efeitos adversos , Qualidade de Vida , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controleRESUMO
The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.
Assuntos
Benzamidinas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Guanidinas , Doenças Vasculares , Humanos , Camundongos , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Glicocálix , Modelos Animais de Doenças , Camundongos Endogâmicos , Necrose/tratamento farmacológicoRESUMO
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.
Assuntos
Glicocálix , Sindecana-1 , Sindecana-1/metabolismo , Glicocálix/metabolismo , Sindecana-3/metabolismo , Sindecana-4/metabolismo , Sindecana-2/metabolismo , Biglicano/metabolismo , Glipicanas/metabolismo , Decorina/metabolismo , Quimiocinas/metabolismo , Anti-Inflamatórios/metabolismoRESUMO
OBJECTIVE: This study aimed to explore the effects of sedative doses of propofol and isoflurane on microcirculation in septic mice compared to controls. Isoflurane, known for its potential as a sedation drug in bedside applications, lacks clarity regarding its impact on the microcirculation system. The hypothesis was that propofol would exert a more pronounced influence on the microvascular flow index, particularly amplified in septic conditions. MATERIAL AND METHODS: Randomized study was conducted from December 2020 to October 2021 involved 60 BALB/c mice, with 52 mice analyzed. Dorsal skinfold chambers were implanted, followed by intraperitoneal injections of either sterile 0.9 % saline or lipopolysaccharide for the control and sepsis groups, respectively. Both groups received propofol or isoflurane treatment for 120 min. Microcirculatory parameters were obtained via incident dark-field microscopy videos, along with the mean blood pressure and heart rate at three time points: before sedation (T0), 30 min after sedation (T30), and 120 min after sedation (T120). Endothelial glycocalyx thickness and syndecan-1 concentration were also analyzed. RESULTS: In healthy controls, both anesthetics reduced blood pressure. However, propofol maintained microvascular flow, differing significantly from isoflurane at T120 (propofol, 2.8 ± 0.3 vs. isoflurane, 1.6 ± 0.9; P < 0.001). In the sepsis group, a similar pattern occurred at T120 without statistical significance (propofol, 1.8 ± 1.1 vs. isoflurane, 1.2 ± 0.7; P = 0.023). Syndecan-1 levels did not differ between agents, but glycocalyx thickness index was significantly lower in the isoflurane-sepsis group than propofol (P = 0.001). CONCLUSIONS: Propofol potentially offers protective action against microvascular flow deterioration compared to isoflurane, observed in control mice. Furthermore, a lower degree of sepsis-induced glycocalyx degradation was evident with propofol compared to isoflurane.
Assuntos
Anestésicos Inalatórios , Isoflurano , Propofol , Sepse , Animais , Camundongos , Propofol/farmacologia , Isoflurano/farmacologia , Microcirculação , Sindecana-1 , Anestésicos Inalatórios/farmacologia , Sepse/tratamento farmacológico , Anestésicos Intravenosos/farmacologiaRESUMO
BACKGROUND: Microvascular dysfunction plays a central role in organ dysfunction during septic shock. Endothelial glycocalyx (eGC) damage could contribute to impaired microcirculation. The aim was to assess whether several eGC-damaged biomarkers are associated with microvascular dysfunction in resuscitated septic shock patients. METHODS: This cross-sectional study included resuscitated septic shock patients (N = 31), and a group of healthy individuals (N = 20). The eGC damage biomarkers measured were syndecan-1 (SDC-1), soluble CD44 (CD44s), hyaluronic acid (HYAL) in blood sample; sulfated glycosaminoglycans (GAGs) in urine sample; and thrombomodulin (TBML) in blood sample as biomarker of endothelial cell damage. Microcirculation was assessed through sublingual videocapillaroscopy using the GlycoCheck™, which estimated the perfused vascular density (PVD); the perfused boundary region (PBR), an inverse parameter of the eGC thickness; and the microvascular health score (MVHS). We defined a low MVHS (<50th percentile in septic patients) as a surrogate for more impaired microvascular function. RESULTS: The SDC-1, CD44s, TBML and GAGs levels were correlated with impaired microvascular parameters (PVD of vessels with diameter < 10 µm, MVHS and flow-adjusted PBR); p < 0.05 for all comparisons, except for GAGs and flow-adjusted PBR. The SDC-1 [78 ng/mL (interquartile range (IQR) 45-336) vs. 48 ng/mL (IQR 9-85); p = 0.052], CD44s [796ρg/mL (IQR 512-1995) vs. 526ρg/mL (IQR 287-750); p = 0.036], TBML [734ρg/mL (IQR 237-2396) vs. 95ρg/mL (IQR 63-475); p = 0.012] and GAGs levels [0.42 ρg/mg (IQR 0.04-1.40) vs. 0.07 ρg/mg (IQR 0.02-0.20); p = 0.024]; were higher in septic patients with more impaired sublingual microvascular function (low MVHS vs. high MVHS). CONCLUSION: SDC-1, CD44s, TBML and GAGs levels were associated with impaired microvascular function in resuscitated septic shock patients.
Assuntos
Biomarcadores , Glicocálix , Receptores de Hialuronatos , Ácido Hialurônico , Microcirculação , Choque Séptico , Sindecana-1 , Trombomodulina , Humanos , Glicocálix/metabolismo , Choque Séptico/fisiopatologia , Choque Séptico/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Sindecana-1/sangue , Estudos Transversais , Receptores de Hialuronatos/metabolismo , Idoso , Trombomodulina/sangue , Ácido Hialurônico/sangue , Estudos de Casos e Controles , Ressuscitação , Glicosaminoglicanos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Angioscopia Microscópica , Microvasos/fisiopatologia , Microvasos/patologia , Adulto , Densidade Microvascular , Soalho Bucal/irrigação sanguíneaRESUMO
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.
Assuntos
Sindecana-1 , Lesão Pulmonar Induzida por Ventilação Mecânica , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Glicocálix/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Pulmão/metabolismoRESUMO
BACKGROUND: In recent years, it has been demonstrated that when the endothelial glycocalyx, composed of proteoglycans, glycosaminoglycans and glycoproteins, is altered or modified, this property is lost, playing a fundamental role in cardiovascular pathologies. Cardiovascular risk factors can destroy the endothelial glycocalyx layer. Exercise has a positive effect on cardiovascular risk factors, but little is known about its direct effect on the integrity of the endothelial layer. METHODS: The Cochrane Library, PubMed, Web of Science and Scopus databases were searched from their inception to June 30, 2022. The DerSimonian and Laird method was used to compute pooled effect size estimates and their respective 95% confidence intervals for the acute effect of exercise (within 24 h) on the endothelial glycocalyx and its components in healthy adults. RESULTS: Ten studies were included in the meta-analysis, with a total of 252 healthy subjects. The types of exercise included were resistance training, interval training, resistance training and maximal incremental exercise, with a duration range of 30-60 min. Glycocalyx assessment times included ranged from 0 to 90 min post-exercise. Our findings showed that endothelial glycocalyx increases after acute effect of exercise in healthy population (.56, 95% CI: .38, .74). The acute effect of exercise on endothelial glycocalyx components were .47 (95% CIs: .27, .67) for glycosaminoglycans, .67 (95% CIs: .08, 1.26) for proteoglycans and .61 (95% CIs: .35, .86) for glycoproteins. CONCLUSIONS: In a healthy population, various types of exercise showed an acute improvement of the endothelial glycocalyx and its individual components.
Assuntos
Endotélio Vascular , Exercício Físico , Glicocálix , Humanos , Glicocálix/metabolismo , Glicocálix/fisiologia , Exercício Físico/fisiologia , Endotélio Vascular/metabolismo , Adulto , Treinamento Resistido , Glicosaminoglicanos/metabolismo , Voluntários Saudáveis , Sindecana-1/metabolismo , Glicoproteínas/metabolismo , Proteoglicanas/metabolismoRESUMO
BACGROUND: Off-pump coronary artery bypass graft (OPCABG) has a high incidence of postoperative systemic inflammation response syndrome (SIRS), and perioperative endothelial glycocalyx layer (EGL) disruption can be one of the predisposing factors. We hypothesized that EGL shedding happened earlier in OPCABG which can influence on postoperative SIRS, and sevoflurane might preserve EGL better than propofol. METHODS: We randomly allocated 50 patients undergoing OPCABG to receive either sevoflurane-sufentanil or propofol-sufentanil anesthesia. Plasma syndecan-1, heparan sulfate (HS), atrial natriuretic peptide (ANP), IL-6, and cardiac troponin I (cTnI) were measured. Blood samples were collected at 6 timepoints: induction (T1), before grafting (T2), after grafting(T3), surgery done (T4), postoperative day1 (POD1,T5) and POD2 (T6). SIRS criteria and sequential organ failure assessment (SOFA) score were examined. RESULTS: There were neither differences of syndecan-1, HS, IL-6 nor of SIRS criteria or SOFA score between the sevoflurane and propofol groups. All patients were pooled as a single group for further statistical analyses, plasma syndecan-1 (P < 0.001) and IL-6 (P < 0.001) increased significantly as a function of time; syndecan-1 increasing correlated significantly with the duration of coronary graft anastomosis (r = 0.329, P = 0.026). Syndecan-1(T3) correlated significantly with ANP(T3) (r = 0.0.354, P = 0.016) and IL-6 (T5) (r = 0.570, P < 0.001). The maximum value of IL-6 correlated significantly with SIRS (r = 0.378, P = 0.010), the maximum value of SOFA score (r = 0.399, P = 0.006) and ICU days (r = 0.306, P = 0.039). The maximum value of SOFA score correlated significantly with the occurrence of SIRS (r = 0.568, P < 0.001) and ICU days (r = 0.338, P = 0.022). CONCLUSIONS: OPCABG intraoperative early EGL shedding caused of grafts anastomosis greatly affected postoperative SIRS and SOFA score, sevoflurane did not clinically preserve EGL better. TRIAL REGISTRATION: ChiCTR-IOR-17012535. Registered on 01/09/2017.
Assuntos
Glicocálix , Propofol , Humanos , Sindecana-1 , Propofol/farmacologia , Sevoflurano , Sufentanil , Interleucina-6 , Inflamação , Síndrome de Resposta Inflamatória SistêmicaRESUMO
The endothelial glycocalyx (EG) is a meshlike network present on the apical surface of the endothelium. Membrane-bound proteoglycans, the major backbone molecules of the EG, consist of glycosaminoglycans attached to core proteins. In addition to maintaining the integrity of the endothelial barrier, the EG regulates inflammation and perfusion and acts as a mechanosensor. The loss of the EG can cause endothelial dysfunction and drive the progression of vascular diseases including diabetic retinopathy. Therefore, the EG presents a novel therapeutic target for treatment of vascular complications. In this review article, we provide an overview of the structure and function of the EG in the retina. Our particular focus is on hyperglycemia-induced perturbations in the glycocalyx structure in the retina, potential underlying mechanisms, and clinical trials studying protective treatments against degradation of the EG.
Assuntos
Diabetes Mellitus , Retinopatia Diabética , Hiperglicemia , Doenças Vasculares , Humanos , Retinopatia Diabética/complicações , Retinopatia Diabética/metabolismo , Glicocálix/metabolismo , Endotélio Vascular/metabolismo , Hiperglicemia/metabolismo , Doenças Vasculares/metabolismo , Retina/metabolismo , Diabetes Mellitus/metabolismoRESUMO
BACKGROUND: Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection. METHODS: This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4-25 µm. MEASUREMENTS AND MAIN RESULTS: Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: - 45.16%; D6: - 35.60%; D7: - 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002). CONCLUSIONS: Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.
Assuntos
COVID-19 , Capilares , Humanos , Síndrome de COVID-19 Pós-Aguda , Estudos Prospectivos , Estado Terminal , COVID-19/metabolismo , SARS-CoV-2 , Glicocálix , MicrocirculaçãoRESUMO
OBJECTIVE: To examine changes in biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress following major open abdominal surgery and the correlation to postoperative morbidity. INTRODUCTION: Major abdominal surgery is associated with high levels of postoperative morbidity. Two possible reasons are the surgical stress response and the impairment of the glycocalyx and endothelial cells. Further, the degree of these responses may correlate with postoperative morbidity and complications. METHODS: A secondary data analysis of prospectively collected data from two cohorts of patients undergoing open liver surgery, gastrectomy, esophagectomy, or Whipple procedure (n = 112). Hemodynamics and blood samples were collected at predefined timestamps and analyzed for biomarkers of glycocalyx shedding (Syndecan-1), endothelial activation (sVEGFR1), endothelial damage (sThrombomodulin (sTM)), and surgical stress (IL6). RESULTS: Major abdominal surgery led to increased levels of IL6 (0 to 85 pg/mL), Syndecan-1 (17.2 to 46.4 ng/mL), and sVEGFR1 (382.8 to 526.5 pg/mL), peaking at the end of the surgery. In contrast, sTM, did not increase during surgery, but increased significantly following surgery (5.9 to 6.9 ng/mL), peaking at 18 h following the end of surgery. Patients characterized with high postoperative morbidity had higher levels of IL6 (132 vs. 78 pg/mL, p = 0.007) and sVEGFR1 (563.1 vs. 509.4 pg/mL, p = 0.045) at the end of the surgery, and of sTM (8.2 vs. 6.4 ng/mL, p = 0.038) 18 h following surgery. CONCLUSION: Major abdominal surgery leads to significantly increased levels of biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress, with the highest levels seen in patients developing high postoperative morbidity.
Assuntos
Células Endoteliais , Interleucina-6 , Humanos , Sindecana-1 , Endotélio , Biomarcadores , GlicocálixRESUMO
The endothelium, a crucial homeostatic organ, regulates vascular permeability and tone. Under physiological conditions, endothelial stimulation induces vasodilator endothelial nitric oxide (eNO) release and prevents adhesion molecule accessibility and leukocyte adhesion and migration into vessel walls. Endothelium dysfunction is a principal event in cardiovascular disorders, including atherosclerosis. Minimal attention is given to an important endothelial cell structure, the endothelial glycocalyx (GCX), a negatively charged heterogeneous polysaccharide that serves as a protective covering for endothelial cells and enables endothelial cells to transduce mechanical stimuli into various biological and chemical activities. Endothelial GCX shedding thus plays a role in endothelial dysfunction, for example by increasing vascular permeability and decreasing vessel tone. Consequently, there is increasing interest in developing therapies that focus on GCX repair to limit downstream endothelium dysfunction and prevent further downstream cardiovascular events. Here, we present diosmin (3',5,7-trihydroxy-4'-methoxyflavone-7-rhamnoglucoside), a flavone glycoside of diosmetin, which downregulates adhesive molecule expression, decreases inflammation and capillary permeability, and upregulates eNO expression. Due to these pleiotropic effects of diosmin on the vasculature, a possible unidentified mechanism of action is through GCX restoration. We hypothesize that diosmin positively affects GCX integrity along with GCX-related endothelial functions. Our hypothesis was tested in a partial ligation left carotid artery (LCA) mouse model, where the right carotid artery was the control for each mouse. Diosmin (50 mg/kg) was administered daily for 7 days, 72 h after ligation. Within the ligated mice LCAs, diosmin treatment elevated the activated eNO synthase level, inhibited inflammatory cell uptake, decreased vessel wall thickness, increased vessel diameter, and increased GCX coverage of the vessel wall. ELISA showed a decrease in hyaluronan concentration in plasma samples of diosmin-treated mice, signifying reduced GCX shedding. In summary, diosmin supported endothelial GCX integrity, to which we attribute diosmin's preservation of endothelial function as indicated by attenuated expression of inflammatory factors and restored vascular tone.
Assuntos
Aterosclerose , Diosmina , Camundongos , Animais , Glicocálix/metabolismo , Diosmina/farmacologia , Diosmina/metabolismo , Células Endoteliais/metabolismo , Aterosclerose/metabolismo , Óxido Nítrico/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Endothelial glycocalyx (EG) is an active player and treatment target in inflammatory-related vascular leakage. The bone marrow mesenchymal stem cells (bMSCs) are promising potential treatments for leakage; however, the therapeutic effect and mechanism of bMSC on EG degradation needs to be elucidated. METHODS: EG degradation and leakage were evaluated in both lipopolysaccharide (LPS)-induced mice ear vascular leakage model and LPS-stimulated human umbilical vein endothelial cells (HUVECs) model treated with bMSCs. Extracellular vesicles (EVs) were extracted from bMSCs and the containing microRNA profile was analyzed. EV and miR let-7-5p were inhibited to determine their function in the therapeutic process. The ABL2 gene was knockdown in HUVECs to verify its role as a therapeutic target in EG degradation. RESULTS: bMSCs treatment could alleviate LPS-induced EG degradation and leakage in vivo and in vitro, whereas EVs/let-7-5p-deficient bMSCs were insufficient to reduce EG degradation. LPS down-regulated the expression of let-7-5p while upregulated endothelial expression of ABL2 in HUVECs and induced EG degradation and leakage. bMSC-EVs uptaken by HUVECs could deliver let-7-5p targeting endothelial ABL2, which suppressed the activation of downstream p38MAPK and IL-6, IL-1ß levels, and thus reversed LPS-induced EG degradation and leakage. CONCLUSION: bMCSs alleviate LPS-induced EG degradation and leakage through EV delivery of miR let-7-5p targeting endothelial ABL2.
Background Inflammation-related Endothelial vascular leakage (EVL) is associated with poor clinical prognosis. Endothelial glycocalyx (EG) is a novel therapeutic target for EVL. bMSCs (Bone Mesenchymal Stem Cells) are potential therapies for EVL, but the effect of bMSCs on EG has not been investigated.Significance bMSCs alleviating EG degradation and leakage was firstly clarified in our LPS-induced vascular leakage mice model. Histology and electrophysiology experiments validated that bMSCs achieve therapeutic effects through paracrine extracellular vesicles (EVs). EV-delivered MicroRNA sequencing revealed that miR let-7-5p down-regulated endothelial ABL2/p38MAPK-related inflammation activation. The bMSC-EV delivered let-7-5p was proved as an effective element in alleviating inflammation-related EG degradation and leakage, providing an executable approach for bMSCs to treat EVL. Video Abstract.
Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Animais , Camundongos , Glicocálix , Lipopolissacarídeos/farmacologia , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , MicroRNAs/genéticaRESUMO
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 ß-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.
Assuntos
Hipertensão Portal , Nefropatias , Ratos , Animais , Receptor A2A de Adenosina , Glicocálix/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hipertensão Portal/metabolismo , Fibrose , Sindecana-1RESUMO
Endothelial glycocalyx is a negatively charged gel-like layer located on the apical surface of endothelial cells. It serves as a selective two-way physical barrier between the flowing blood and the endothelium, which regulates the access of macromolecules and of blood cells to the endothelial surface. In addition, endothelial glycocalyx plays a major role in sensing mechanical signals generated by the blood flow and transducing these signals to maintain endothelial functions; Thus, dysfunction or disruption of endothelial glycocalyx in pathological condition leads to endothelial dysfunction and contributes to the development of vascular diseases. In this review, we discuss the impact of atherosclerosis with the following viewpoints: (i) hypercholesterolemic effects on endothelial glycocalyx degradation in animal models and human patients, (ii) disruption of endothelial glycocalyx by atherogenic lipoproteins, (iii) proatherogenic disturbed flow effects on endothelial glycocalyx degradation, (iv) pathological consequences of the loss of glycocalyx integrity in atherogenesis, and (v) therapeutic effect of glycocalyx supplementation on atherosclerosis development. Additionally, we also discuss recent studies in pathological effects of obesity on the disruption of endothelial glycocalyx.
Assuntos
Aterosclerose , Células Endoteliais , Animais , Humanos , Células Endoteliais/metabolismo , Glicocálix/metabolismo , Endotélio Vascular/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Obesidade/metabolismo , Obesidade/patologiaRESUMO
The endothelial glycocalyx is an extracellular matrix that coats the endothelium and extends into the lumen of blood vessels, acting as a barrier between the vascular wall and blood flowing through the vessel. This positioning of the glycocalyx permits a variety of its constituents, including the major endothelial proteoglycans glypican-1 and syndecan-1, as well as the major glycosaminoglycans heparan sulfate and hyaluronic acid, to contribute to the processes of mechanosensation and subsequent mechanotransduction following such stimuli as elevated shear stress. To coordinate the vast array of processes that occur in response to physical force, the glycocalyx interacts with a plethora of membrane and cytoskeletal proteins to carry out specific signaling pathways resulting in a variety of responses of endothelial cells and, ultimately, blood vessels to mechanical force. This review focuses on proposed glycocalyx-protein relationships whereby the endothelial glycocalyx interacts with a variety of membrane and cytoskeletal proteins to transduce force into a myriad of chemical signaling pathways. The established and proposed interactions at the molecular level are discussed in context of how the glycocalyx regulates membrane/cytoskeletal protein function in the many processes of endothelial mechanotransduction.