COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

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Effect of Congo Red on Blood Platelets and Leucocytes of Rabbits and Cats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653701 ◽

1971 ◽

Vol 26 (03) ◽

pp. 488-492 ◽

Cited By ~ 3

Author(s):

Th B. Tschopp ◽

H.-R Baumgartner ◽

A Studer

Keyword(s):

Fatty Acids ◽

Congo Red ◽

Platelet Rich Plasma ◽

Blood Platelets ◽

Severe Thrombocytopenia ◽

Ultrastructural Alterations ◽

Indirect Mechanism

SummaryIn rabbits and cats Congo red administered intravenously causes severe thrombocytopenia and ultrastructural alterations of platelets and leucocytes, similar to those produced by some fatty acids and endotoxin. Transient leucopenia is followed by leucocytosis. In contrast, incubation of Congo red in citrated blood or platelet rich plasma has no effect. Therefore, an indirect mechanism is postulated to explain the in vivo effect of Congo red.

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Protective Effect of Vitamin E on Immune Triggered, Granulocyte Mediated Endothelial Injury

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661027 ◽

1984 ◽

Vol 51 (01) ◽

pp. 089-092 ◽

Cited By ~ 24

Author(s):

M A Boogaerts ◽

J Van de Broeck ◽

H Deckmyn ◽

C Roelant ◽

J Vermylen ◽

...

Keyword(s):

Vitamin E ◽

Protective Effect ◽

Umbilical Vein ◽

Endothelial Damage ◽

Endothelial Injury ◽

Mediated Effects ◽

Anti Oxidant ◽

Endothelial Cell Cultures ◽

Vitro Model

SummaryThe effect of alfa-tocopherol on the cell-cell interactions at the vessel wall were studied, using an in vitro model of human umbilical vein endothelial cell cultures (HUEC). Immune triggered granulocytes (PMN) will adhere to and damage HUEC and platelets enhance this PMN mediated endothelial injury. When HUEC are cultured in the presence of vitamin E, 51Cr-leakage induced by complement stimulated PMN is significantly decreased and the enhanced cytotoxicity by platelets is completely abolished (p <0.001).The inhibition of PMN induced endothelial injury is directly correlated to a diminished adherence of PMN to vitamin E- cultured HUEC (p <0.001), which may be mediated by an increase of both basal and stimulated endogenous prostacyclin (PGI2) from alfa-tocopherol-treated HUEC (p <0.025). The vitamin E-effect is abolished by incubation of HUEC with the irreversible cyclo-oxygenase inhibitor, acetylsalicylic acid, but the addition of exogenous PGI2 could not reproduce the vitamin E-mediated effects.We conclude that vitamin E exerts a protective effect on immune triggered endothelial damage, partly by increasing the endogenous anti-oxidant potential, partly by modulating intrinsic endothelial prostaglandin production. The failure to reproduce vitamin E-protection by exogenously added PGI2 may suggest additional, not yet elucidated vitamin E-effects on endothelial metabolism.

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Faculty Opinions recommendation of The Wnt/beta-catenin pathway posteriorizes neural tissue in Xenopus by an indirect mechanism requiring FGF signalling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1003720.39404 ◽

2002 ◽

Author(s):

Gary Schoenwolf

Keyword(s):

Neural Tissue ◽

Beta Catenin ◽

Indirect Mechanism ◽

Fgf Signalling

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Faculty Opinions recommendation of Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718088975.793483456 ◽

2013 ◽

Author(s):

Vinicio de Jesus Perez

Keyword(s):

Pulmonary Hypertension ◽

Leukotriene B4 ◽

Endothelial Injury

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Impact of markers of endothelial injury and hypercoagulability on systemic lupus erythematosus

Lupus ◽

10.1177/0961203319899478 ◽

2020 ◽

Vol 29 (2) ◽

pp. 182-190

Author(s):

W Batista Cicarini ◽

R C Figueiredo Duarte ◽

K Silvestre Ferreira ◽

C de Mello Gomes Loures ◽

R Vargas Consoli ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Endothelial Injury ◽

Control Group ◽

Systemic Lupus ◽

Low Concentrations ◽

The Relationship

We have explored the relationship between possible hemostatic changes and clinical manifestation of the systemic lupus erythematosus (SLE) as a function of greater or lesser disease activity according to Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) criteria. Endothelial injury and hypercoagulability were investigated in patients with SLE by measuring thrombomodulin (TM), D-dimer (DDi) and thrombin generation (TG) potential. A total of 90 participants were distributed into three groups: 1) women with SLE presenting with low disease activity (laSLE) (SLEDAI-2K ≤ 4), 2) women with SLE presenting with moderate to high disease activity (mhaSLE) (SLEDAI-2K > 4), and 3) a control group comprising healthy women. Levels of TM and DDi were higher both in the laSLE and mhaSLE groups compared to controls and in mhaSLE compared to the laSLE group. With respect to TG assay, lagtime and endogen thrombin potential, low concentrations of tissue factor provided the best results for discrimination among groups. Analysis of these data allow us to conclude that TM, DDi and TG are potentially useful markers for discriminating patients with very active from those with lower active disease. Higher SLE activity may cause endothelial injury, resulting in higher TG and consequently a hypercoagulability state underlying the picture of thrombosis common in this inflammatory disease.

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Transient endothelial injury and release of lupus anticoagulant in COVID-19

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02485-5 ◽

2021 ◽

Author(s):

Antonin Trimaille ◽

Benjamin Marchandot ◽

Walid Oulehri ◽

Adrien Carmona ◽

Olivier Vollmer ◽

...

Keyword(s):

Lupus Anticoagulant ◽

Endothelial Injury

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Potential Role and Impact of Peripheral Blood Mononuclear Cells in Radiographic Axial Spondyloarthritis-Associated Endothelial Dysfunction

Diagnostics ◽

10.3390/diagnostics11061037 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1037

Author(s):

Patricia Ruiz-Limon ◽

Maria L. Ladehesa-Pineda ◽

Clementina Lopez-Medina ◽

Chary Lopez-Pedrera ◽

Maria C. Abalos-Aguilera ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Axial Spondyloarthritis ◽

Endothelial Injury ◽

In Vitro Studies ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

Endothelial dysfunction (ED) is well known as a process that can lead to atherosclerosis and is frequently presented in radiographic axial spondyloarthritis (r-axSpA) patients. Here, we investigated cellular and molecular mechanisms underlying r-axSpA-related ED, and analyzed the potential effect of peripheral blood mononuclear cells (PBMCs) in promoting endothelial injury in r-axSpA. A total of 30 r-axSpA patients and 32 healthy donors (HDs) were evaluated. The endothelial function, inflammatory and atherogenic profile, and oxidative stress were quantified. In vitro studies were designed to evaluate the effect of PBMCs from r-axSpA patients on aberrant endothelial activation. Compared to HDs, our study found that, associated with ED and the plasma proatherogenic profile present in r-axSpA, PBMCs from these patients displayed a pro-oxidative, proinflammatory, and proatherogenic phenotype, with most molecular changes noticed in lymphocytes. Correlation studies revealed the relationship between this phenotype and the microvascular function. Additional in vitro studies confirmed that PBMCs from r-axSpA patients promoted endothelial injury. Altogether, this study suggests the relevance of r-axSpA itself as a strong and independent cardiovascular risk factor, contributing to a dysfunctional endothelium and atherogenic status by aberrant activation of PBMCs. Lymphocytes could be the main contributors in the development of ED and subsequent atherosclerosis in this pathology.

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