Berberine alleviates endothelial glycocalyx degradation and promotes glycocalyx restoration in LPS-induced ARDS.

In the pathogenesis of acute respiratory distress syndrome (ARDS), an increase in vascular endothelial permeability may trigger pulmonary edema and ultimately lead to respiratory failure. Endothelial glycocalyx damage is an important factor that causes an increase in vascular endothelial permeability. Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis, a plant used in traditional Chinese medicine that exerts multiple pharmacological effects. In this study, pretreatment with BBR inhibited the increase in vascular endothelial permeability in mice with lipopolysaccharide (LPS)-induced ARDS. BBR pretreatment inhibited the shedding of syndecan-1 (SDC-1) and heparan sulfate (HS), which are important components of the endothelial glycocalyx that lessen endothelial glycocalyx damage. BBR further significantly inhibited increases in important endothelial glycocalyx damage factors, including reactive oxygen species (ROS), heparanase (HPA), and matrix metalloproteinase 9 (MMP9) in LPS-induced ARDS mice and in LPS-stimulated human umbilical vein endothelial cells. BBR pretreatment also decreased the production of pro-inflammatory cytokines TNF-α, IL-1ß, IL-6, and inhibited NF-κB signaling pathway activation in LPS-induced ARDS. In addition, BBR promoted the recovery of SDC-1 and HS content in injured endothelial glycocalyx after LPS treatment and accelerated its restoration. This is the first report of BBR maintaining the integrity of endothelial glycocalyx. These results provide a new theoretical basis for the use of BBR in the treatment of ARDS and other diseases related to endothelial glycocalyx damage.

Effects of respiratory muscle training on endothelium and oxidative stress biomarkers in hemodialysis patients: A randomized clinical trial.

INTRODUCTION: Hemodialysis (HD) patients have altered pulmonary function and this is associated with impaired endothelial function and cardiovascular events. Respiratory muscle training (RMT) has the potential to improve cardiovascular outcomes in patients undergoing maintenance HD. Here, we evaluated the effects of RMT on endothelium/glycocalyx, oxidative stress biomarkers and pulmonary function test in HD patients. METHODS: This is a randomized controlled clinical trial including 41 patients undergoing thrice-weekly maintenance HD. Patients were randomly assigned at a 2:1 ratio to receive or not RMT during HD sessions for 8 weeks. Main outcomes were changes in levels of the biomarkers related to endothelium activation (vascular cell adhesion molecule 1, VCAM-1, and intercellular adhesion molecule 1, ICAM-1), glycocalyx derangement (syndecan-1), aberrant angiogenesis (angiopoietin-2) and oxidative stress (malondialdehyde) compared to baseline. Also, maximal inspiratory/expiratory pressure (MIP, MEP), Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were evaluated. Other outcomes included changes in functional capacity and pulmonary function test. We also performed a post-hoc analysis of plasma endothelin-1 levels. RESULTS: Of 56 randomly assigned patients, 41 were included in the primary final analyses. RMT increased all pulmonary function parameters evaluated and significantly reduced plasma syndecan-1 levels at 8 weeks compared to placebo (between-group difference: -84.5; 95% CI, -148.1 to -20.9). Also, there was a reduction in plasma levels of angiopoietin-2 (between-group difference: -0.48; 95% CI, -1.03 to -0.097). Moreover, there was a significant reduction in mean blood pressure at rest (between-group difference: -12.2; 95%CI, -17.8 to -6.6) associated with a reduction in endothelin-1 levels (between-group difference: -0.164; 95% CI, -0.293 to -0.034). There was no difference regarding biomarkers of endothelial activation or oxidative stress. CONCLUSION: A short-term RMT program ameliorate FVC, FEV1 and reduces syndecan-1 and angiopoietin-2 biomarker levels. Finally, better blood pressure control was attained during training and it was associated with a reduction in endothelin-1 levels.

Microvascular permeability to water is independent of shear stress, but dependent on flow direction.

Endothelial cells in a cultured monolayer change from a "cobblestone" configuration when grown under static conditions to a more elongated shape, aligned with the direction of flow, after exposure to sustained uniform shear stress. Sustained blood flow acts to protect regions of large arteries from injury. We tested the hypothesis that the stable permeability state of individually perfused microvessels is also characteristic of flow conditioning. In individually perfused rat mesenteric venular microvessels, microvascular permeability, measured as hydraulic conductivity (Lp), was stable [mean 1.0 × 10(-7) cm/(s × cmH2O)] and independent of shear stress (3-14 dyn/cm(2)) for up to 3 h. Vessels perfused opposite to the direction of normal blood flow exhibited a delayed Lp increase [ΔLp was 7.6 × 10(-7) cm/(s × cmH2O)], but the increase was independent of wall shear stress. Addition of chondroitin sulfate and hyaluronic acid to perfusates increased the shear stress range, but did not modify the asymmetry in response to flow direction. Increased Lp in reverse-perfused vessels was associated with numerous discontinuities of VE-cadherin and occludin, while both proteins were continuous around the periphery of forward-perfused vessels. The results are not consistent with a general mechanism for graded shear-dependent permeability increase, but they are consistent with the idea that a stable Lp under normal flow contributes to prevention of edema formation and also enables physiological regulation of shear-dependent small solute permeabilities (e.g., glucose). The responses during reverse flow are consistent with reports that disturbed flows result in a less stable endothelial barrier in venular microvessels.

Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats.

Vascular permeability and endothelial glycocalyx were examined in young adult spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and Wistar Kyoto rats (WKY) as a control, in order to determine earlier changes in the blood-brain barrier (BBB) in the hypothalamus in chronic hypertension. These rats were injected with horseradish peroxidase (HRP) as an indicator of vascular permeability. Brain slices were developed with a chromogen and further examined with cationized ferritin, a marker for evaluating glycocalyx. Staining for HRP was seen around vessels in the hypothalamus of SHR and SHRSP, but was scarce in WKY. The reaction product of HRP appeared in the abluminal pits of endothelial cells and within the basal lamina of arterioles, showing increased vascular permeability in the hypothalamus of SHR and SHRSP, whereas there were no leaky vessels in the frontal cortex of SHR and SHRSP, or in both areas of WKY. The number of cationized ferritin particles binding to the capillary endothelial cells was decreased in the hypothalamus of SHR and SHRSP, while the number decreased in the frontal cortex of SHRSP, compared with those in WKY. Cationized ferritin binding was preserved in some leaky arterioles, while it was scarce or disappeared in other leaky vessels. These findings suggest that BBB disruption occurs in the hypothalamus of 3-month-old SHR and SHRSP, and that endothelial glycocalyx is markedly damaged there without a close relationship to the early changes in the BBB.