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The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.

Pulmonary endothelial cells (ECs) are an essential component of the gas exchange machinery of the lung alveolus. Despite this, the extent and function of lung EC heterogeneity remains incompletely understood. Using single-cell analytics, we identify multiple EC populations in the mouse lung, including macrovascular endothelium (maEC), microvascular endothelium (miECs), and a new population we have termed Car4-high ECs. Car4-high ECs express a unique gene signature, and ligand-receptor analysis indicates they are primed to receive reparative signals from alveolar type I cells. After acute lung injury, they are preferentially localized in regenerating regions of the alveolus. Influenza infection reveals the emergence of a population of highly proliferative ECs that likely arise from multiple miEC populations and contribute to alveolar revascularization after injury. These studies map EC heterogeneity in the adult lung and characterize the response of novel EC subpopulations required for tissue regeneration after acute lung injury. Animal lungs are filled with tiny air sacks called alveoli, where the gas exchanges that keep organisms alive can take place. Small blood vessels known as capillaries come in close contact with the alveoli, allowing oxygen to be extracted from the air into the blood, and carbon dioxide to be released from the blood into the air. The cells that line the inside of these capillaries (known as pulmonary endothelial cells) are important actors in these exchanges. After having been damaged, for example by viruses like influenza, the lungs need to regenerate and create new capillaries. Yet, it was still unclear how pulmonary endothelial cells participate in the healing process, and if capillaries contain several populations of endothelial cells that play different roles. To investigate this question, Niethamer et al. used an approach called single-cell analytics to examine individual endothelial cells in the alveoli of mice infected with influenza. This revealed that different subtypes of endothelial cells exist in capillaries, and that some may be able to perform slightly different jobs during lung recovery. Niethamer et al. found that all subtypes could quickly multiply after injury to create more endothelial cells and re-establish gas exchanges. However, one newly identified group (called Car4-high ECs) was particularly primed to receive orders from damaged alveoli. These cells were also often found at the sites where the alveoli were most injured. Lung injuries are a major cause of death worldwide. Understanding how pulmonary endothelial cells work when the organ is both healthy and injured should help to find ways to boost repair, and to create therapies that could target these cells.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 + T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 + T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities. Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

Aims/hypothesis Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties. Methods Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TERalb) and hyaluronan catabolism were assessed as measures of vascular permeability. Results Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TERalb was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p < 0.05). In line, a trend towards TERalb normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group. Conclusion/interpretation Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk. Trial registration www.trialregister.nl NTR780/http://isrctn.org ISRCTN82695186 Funding An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037)

Endothelial dysfunction is a characteristic of systemic arterial hypertension (SAH) and an early marker of atherosclerosis. Aerobic exercise training (AT) improves endothelial function. However, the effects of resistance training (RT) and combined training (CT) on endothelial function remain controversial in individuals with SAH. We determined the effects of AT, RT, and CT on endothelial function and systolic (SBP)/diastolic blood pressure (DBP) in individuals with prehypertension or hypertension. Forty-two participants (54 ± 11 y, resting SBP/DBP 137 ± 9/86 ± 6 mmHg) were randomly allocated into AT (n = 14, 40 min of cycling, 50-75% heart rate reserve), RT (n = 14, 6 resistance exercises, 4 × 12 repetitions, 60% maximum strength) and CT (n = 14, 2 × 12 repetitions of RT + 20 min of AT). All participants performed a 40-minute exercise session twice a week for 8 weeks. Endothelial function was evaluated by brachial artery flow-mediated dilation (FMD). Blood pressure was evaluated through ambulatory monitoring for 24 hours. After 8 weeks of exercise training, blood pressure was reduced in all 3 groups: -5.1 mmHg in SBP (95%CI -10.1, 0.0; p = 0.003) in AT; -4.0 mmHg in SBP (95%CI -7.8, -0.5; p = 0.027) in RT; and -3.2 mmHg in DBP (95%CI -7.9, 1.5; p = 0.001) in CT. All 3 exercise training modalities produced similar improvements in FMD: + 3.2% (95%CI 1.7, 4.6) (p < 0.001) in AT; + 4.0% (95%CI 2.1, 5.7) (p < 0.001) in RT; and +6.8% (95%CI 2.6, 11.1) (p = 0.006) in CT. In conclusion, different exercise training modalities were similarly effective in improving endothelial function but impacts on ambulatory blood pressure appear to be variable in individuals with prehypertension or hypertension.

GLP-1 improves hyperglycemia, and it has been reported to have favorable effects on atherosclerosis. However, it has not been fully elucidated whether GLP-1 is able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of the GLP-1 analogue, liraglutide on endothelial function and glycemic metabolism compared with insulin glargine therapy. In this multicenter, prospective randomized parallel-group comparison study, 31 diabetic outpatients (aged 60.3 ± 10.3 years with HbA1c levels of 8.6 ± 0.8%) with current metformin and/or sulfonylurea treatment were enrolled and randomly assigned to receive liraglutide or glargine therapy once daily for 14 weeks. Flow mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force Monitor), and serum metabolic markers were assessed before and after the treatment period. A greater reduction (worsening) in %FMD was observed in the glargine group, although this change was not statistically different from the liraglutide group (liraglutide; 5.7 to 5.4%, glargine 6.7 to 5.7%). The augmentation index, C-peptide index, derivatives of reactive oxygen metabolites and BMI were significantly improved in the liraglutide group. Central systolic blood pressure and NT-proBNP also tended to be improved in the liraglutide-treated group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Regardless of glycemic improvement, early liraglutide therapy did not affect endothelial function but may provide favorable effects on beta-cell function and cardioprotection in type 2 diabetics without advanced atherosclerosis. UMIN Clinical Trials Registry System as trial ID UMIN000005331.

To identify pre/perioperative variables that shape endothelial cell loss (ECL) after uncomplicated Descemet membrane endothelial keratoplasty (DMEK). This retrospective study included all consecutive patients with Fuchs endothelial corneal dystrophy who underwent DMEK surgery without perioperative or postoperative complications in 2015-2023 and were followed for 12 months. To identify covariates that predicted 12-month ECL, primary hierarchical multivariable analysis was conducted with 12 variables: patient age and sex; donor age; preoperative axial length, visual acuity, central corneal thickness, and graft endothelial cell density; endotamponade with sulfur hexafluoride (SF6) or air; triple-DMEK or pseudophakic-DMEK; operative time; graft marking; and rebubbling. 137 eyes (112 patients) were included. Multivariable analysis showed that SF6 predicted 13.6 ± 3.4% greater ECL vs. air (p < 0.0001) and accounted for 10% of total ECL variation. Longer operative time and multiple (≥2) rebubbling also predicted 0.4 ± 0.7% (p = 0.046) and 11.7 ± 5.1% (p = 0.02) higher ECL, respectively. SF6 significantly reduced rebubbling on univariable analysis (13% vs. 41% for air, p = 0.01). SF6 use for endotamponade may increase ECL after DMEK. There is an urgent need for randomized controlled trials that estimate the relative disadvantages (endothelial toxicity) and advantages (less bothersome rebubbling) of SF6. ClinicalTrials.gov Identifier: NCT02535819.

Adherence to the Mediterranean diet (MD) is associated with reduced morbidity and mortality due to cardiovascular disease. However, how the MD exerts its effects is not fully known. Aim: To assess the 12-month effects of two enhanced MDs compared to a low-fat diet on inflammatory biomarkers related to atherosclerosis and plaque vulnerability in a subcohort of the PREDIMED (Prevencion con Dieta Mediterranea) study. Methods: A total of 164 participants at high risk for cardiovascular disease were randomized into three diet groups: MD supplemented with 50 mL/d of extra virgin olive oil (MD+EVOO) or 30 g/d of nuts (MD+Nuts) and a low-fat diet. Changes in classical cardiovascular risk factors, inflammatory biomarkers of atherosclerosis and plaque vulnerability were measured after 12 months of intervention. Results: Compared to participants in the low-fat diet group, those receiving MD+EVOO and MD+Nuts showed a higher decrease in systolic (6 mmHg)and diastolic (3 mmHg) blood pressure (P = 0.02; both), as well as a reduction of 10% and 8% in LDL-cholesterol (P = 0.04), respectively. Patients in the MD+Nuts group showed a significant reduction of 34% in CD40 expression on monocyte surface compared to low-fat diet patients (P = 0.03). In addition, inflammatory biomarkers related to plaque instability such as C-reactive protein and interleukin-6 were reduced by 45% and 35% and 95% and 90% in the MD+EVOO and MD+Nuts groups, respectively (P<0.05; all) compared to the low-fat diet group. Likewise, sICAM and Pselectin were also reduced by 50% and 27%, respectively in the MD+ EVOO group (P = 0.04) and P-selectin by 19% in MD+Nuts group (P = 0.04) compared to the low-fat diet group. Conclusions: Adherence to the MD is associated with an increase in serum markers of atheroma plaque stability which may explain, at least in part, the protective role of MD against ischemic heart disease.

Background. Shedding of the endothelial glycocalyx layer (EGL) is known to occur during major surgery, but its degradation associated with minimally invasive video-assisted thoracoscopy (VATS) remains unclear. We investigated if serum biomarkers of EGL disruption were elevated during VATS lobectomy, and whether the urinary trypsin inhibitor (UTI) ulinastatin exerted a protective effect during this procedure. Materials and Methods. Sixty ASA II-III lung cancer patients undergoing elective VATS lobectomy were divided equally into UTI and control groups. UTI group patients received intravenous UTI during surgery. Serum levels of syndecan-1 and heparan sulfate were examined before (T0) and at the end of surgery (T1). Serum albumin and hemoglobin were measured before surgery (BOD) and on the first postoperative day (POD1). Results. In control group, syndecan-1 levels were significantly elevated at T1 compared with T0 (3.77±3.15 versus 4.28±3.30, P=0.022⁎) and increased even more significantly in patients whose surgery lasted >3 h (3.28±2.84 versus 4.31±3.39, P=0.003⁎⁎). Serum albumin levels on POD1 were significantly lower in control group compared with UTI group (32.63±4.57 versus 35.76±2.99, P=0.031⁎). Conclusion. EGL degradation occurs following VATS lobectomy. UTI can alleviate this shedding, thus helping preserve normal vascular permeability. Trail Registration. This trial is registered with ChiCTR-IOC-17010416 (January 13, 2017).

Introduction Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis. Methods A post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial-derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database. Results Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P <0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31). Conclusions In our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis. Trial registration Clinicaltrials.gov number: NCT00962156 . Registered 13 July 2009.