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(1) Damage to the endothelial glycocalyx (eGC), a protective layer lining the endothelial luminal surface, is associated with chronic kidney disease (CKD), which leads to a worsening of cardiovascular outcomes in these patients. Currently, there are no targeted therapeutic approaches. Whether the dietary supplement Endocalyx TM (ECX) protects against endothelial damage caused by uremic toxins is unknown. (2) We addressed this question by performing atomic force microscopy measurements on living endothelial cells. We examined the effect of ECX on eGC thickness at baseline and with pooled serum from hemodialysis patients. ECX was also successfully administered in vivo in mice, in which eGC was assessed using perfused boundary region measurements by intravital microscopy of cremasteric vessels. (3) Both ECX and fucoidan significantly improved baseline eGC thickness. Our data indicate that these effects are dependent on ERK/MAPK and PI3K signaling. After incubation with eGC damaging serum from dialysis patients, ECX increased eGC height. Intravital microscopy in mice revealed a relevant increase in baseline eGC dimensions after feeding with ECX. (4) We identified a dietary supplement containing glycocalyx substrates and fucoidan as potential mediators of eGC preservation in vitro and in vivo. Our findings suggest that fucoidan may be an essential component responsible for protecting the eGC in acute settings. Moreover, ECX might contribute to both protection and rebuilding of the eGC in the context of CKD.

Background: Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown., Methods: ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells., Results: Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels., Conclusion: Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH., Competing Interests: Conflict of interest: L. Hobohm reports personal fees for lectures from MSD and Actelion, outside the submitted work. Conflict of interest: S. Kölmel has nothing to disclose. Conflict of interest: C. Niemann has nothing to disclose. Conflict of interest: P. Kümpers has nothing to disclose. Conflict of interest: V.J. Krieg has nothing to disclose. Conflict of interest: M.L. Bochenek has nothing to disclose. Conflict of interest: A.H. Lukasz has nothing to disclose. Conflict of interest: Y. Reiss has nothing to disclose. Conflict of interest: K-H. Plate has nothing to disclose. Conflict of interest: C. Liebetrau reports personal fees for lectures and consultancy from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer–Bristol-Myers Squibb and Thermo-Fisher, outside the submitted work. Conflict of interest: C.B. Wiedenroth reports personal fees for lectures and consultancy from Actelion, Bayer, Pfizer, BTG and MSD, outside the submitted work. Conflict of interest: S. Guth reports personal fees for lectures and consultancy from Actelion, Bayer, GlaxoSmithKline, Pfizer and MSD, outside the submitted work. Conflict of interest: T. Münzel has nothing to disclose. Conflict of interest: G. Hasenfuß reports personal fees for lectures and consultancy from AstraZeneca, Corvia, Impulse Dynamics, Novartis, Servier, Berlin Chemie and Vifor Pharma; and editor honoraria from Springer International Publishing AG. Conflict of interest: P. Wenzel has nothing to disclose. Conflict of interest: E. Mayer reports personal fees for lectures and consultancy from Actelion, Bayer, MSD and Pfizer, outside the submitted work. Conflict of interest: S.V. Konstantinides reports grants from German Federal Ministry of Education and Research (BMBF 01EO1003 and BMBF 01EO1503), during the conduct of the study; personal fees for consultancy and lectures from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, MSD and Pfizer–Bristol-Myers Squibb; and institutional grants from Actelion, Bayer, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer–Bristol-Myers Squibb, outside the submitted work. Conflict of interest: K. Schäfer has nothing to disclose. Conflict of interest: M. Lankeit reports grants from German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503), during the conduct of the study; personal fees for consultancy and lectures from Actelion, Bayer, BRAHMS–Thermo-Fisher Scientific, Daiichi-Sankyo, MSD and Pfizer–Bristol-Myers Squibb, and research funding from BRAHMS–Thermo-Fisher Scientific., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Deterioration of the endothelial glycocalyx (eGC), a protective carbohydrate-rich layer lining the luminal surface of the endothelium, plays a key role in vascular barrier dysfunction and eventually organ-failure in systemic inflammatory response syndrome and sepsis. Early detection of glycocalyx damage could thus become an important goal in critical care. This study was designed to determine the feasibility and reproducibility of quantitative, real-time glycocalyx measurements performed at bedside in the emergency room (ER) and intensive care unit (ICU)., Methods: The observational study included 70 patients admitted to the ER or ICU of a university hospital. A physician and the nurse in charge of the patient performed sublingual microcirculatory measurements using sidestream dark field (SDF) imaging. A novel data acquisition and analysis software (GlycoCheck™) was used to analyze the perfused boundary region (PBR), an inverse parameter of endothelial glycocalyx dimensions in vessels with diameters of between 5 and 25 μm., Results: The method showed a good intra-observer reproducibility. Specifically, intraclass correlation coefficient analysis showed an excellent reproducibility between the physician's measurements (0.77 [CI 95%: 0.52-0.89]). The bias between the two PBRs was - 0.077 ± 0.24 μm. Moreover, there were no significant differences in the PBR values obtained by the nurses when compared to those reported by the physician (regarded as the "gold standard" measurement). Intraclass correlation coefficient analysis showed excellent reproducibility between the nurses' and physician's PBRs (0.75 [95% CI: 0.52-0.87]). The mean difference between the two PBRs (i.e., the bias) was 0.007 ± 0.25 μm. The nurses' PBR assessment had a 90% sensitivity (95% CI: 60-99%) and 90% specificity (95% CI: 80-93%) to identify a severely impaired glycocalyx., Conclusion: Glycocalyx dimensions can be measured at patients' bedside precisely by non-invasive assessment of the PBR. This assessment could become part of standard monitoring and contribute to clinical decision-making and resuscitation protocols in clinical trials and daily practice.