Mild COVID-19 and Impaired Blood Cell–Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics?

Abstract Background Current coronavirus disease 2019 (COVID-19) pandemic reveals thrombotic, vascular, and endothelial dysfunctions at peak disease. However, the duration, degree of damage, and appropriate long-term use of antithrombotic strategies are unclear. Most COVID data are yielded from random clinical observations or autopsy of postmortem samples, while precise blood cellular data in survivors are insufficient. Methods We analyzed erythrocytes, circulating endothelial cells, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n = 31) and matched healthy controls (n = 32) on admission and at hospital discharge. Results All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endothelial cells was significantly (40–100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. COVID-19 also provoked formation of stacked aggregated erythrocytes capable of clogging microvascular bed and of diminishing oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining intracellular penetration of SARS-CoV-2 where it may be replicated and returned to circulation. Conclusion These observational and descriptive data suggest that persistent viral cell injury may cause blood vessel damage; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. There is a residual blood cell damage following the acute phase in some COVID-19 survivors. Controlled outcome-driven trials are urgently needed for exploring optimal use of long-term antithrombotics and vascular protection strategies even after mild COVID-19.

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CYCLOSPORIN A (CyA) INDUCED ENDOTHELIAL CELL INJURY

10.1055/s-0038-1644123 ◽

1987 ◽

Cited By ~ 3

Author(s):

C Zoja ◽

L Furci ◽

F Ghilardi ◽

P Zilio ◽

A Benigni ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Injury ◽

Cell Damage ◽

Chronic Administration ◽

Endothelial Damage ◽

Vascular Damage ◽

Cell Detachment ◽

Aortic Endothelial Cells ◽

Specific Increase ◽

Marked Cell

The chronic administration of CyA to animals and humans to prevent graft rejection may induce renal arteriolar damage resembling hemolytic uremic syndrome (HUS). This is a syndrome of vascular damage with thrombotic occlusions of the microcirculation. Endothelial damage is considered the first event in the pathogenetic cascade leading to HUS. We have used bovine aortic endothelial cells in culture to address the issue of CyA-induced arteriolar damage. CyA-induced a time (1-24 hours) and dose (1-50 μM) dependent cell damage. CyA-induced injury was characterized by an early cell detachment followed by lysis as documented by the increase in LDH and Cr release. 1 μM CyA did not induce cell detachment and lysis was evident only after prolonged incubations. 10 and 50 μM CyA both induced marked cell detachment and lysis: lysis started 3 hours after incubation of endothelial cells with CyA and was maximal at the end of 24 hour incubation (LDH release, percent specific increase over control values: 10 μM CyA, 47%; 50 μM CyA, 70%; 51 Cr release, percent specific increase over control values: 10 μM CyA, 28%; 50 μM CyA, 34%). CyA-induced injury was associated with dose- and time-depedent increase in prostacyclin (PGI2) and thromboxane A2 (TxA2) release by endothelial cells exposed to 10 and 50 μM CyA. CyA-induced generation of PGI2 and TxA2 was inhibited when the incubations were carried-on in the presence of acetyl salicilic acid (500 μM). These studies indicate that CyA exerts a direct toxic effect on endothelial cells and might help to understand the pathogenesis of CyA-induced vascular damage.

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Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01187.2003 ◽

2004 ◽

Vol 287 (6) ◽

pp. H2468-H2477 ◽

Cited By ~ 79

Author(s):

Nader G. Abraham ◽

Rita Rezzani ◽

Luigi Rodella ◽

Adam Kruger ◽

Derek Taller ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Heme Oxygenase ◽

Defense Mechanism ◽

Cell Damage ◽

Vascular Complications ◽

Diabetic Rats ◽

Circulating Endothelial Cells ◽

Heme Oxygenase 1 ◽

Cell Physiology

Heme oxygenase (HO)-1 represents a key defense mechanism against oxidative injury. Hyperglycemia produces oxidative stress and various perturbations of cell physiology. The effect of streptozotocin (STZ)-induced diabetes on aortic HO activity, heme content, the number of circulating endothelial cells, and urinary 8-epi-isoprostane PGF2α(8-Epi) levels in control rats and rats overexpressing or underexpressing HO-1 was measured. HO activity was decreased in hyperglycemic rats. Hyperglycemia increased urinary 8-Epi, and this increase was augmented in rats underexpressing HO-1 and diminished in rats overexpressing HO-1. The number of detached endothelial cells and O2−formation increased in diabetic rats and in hyperglycemic animals underexpressing HO-1 and decreased in diabetic animals overexpressing HO-1 compared with controls. These data demonstrate that HO-1 gene transfer in hyperglycemic rats brings about a reduction in O2−production and a decrease in endothelial cell sloughing. Upregulation of HO-1 decreases oxidant production and endothelial cell damage and shedding and may attenuate vascular complications in diabetes.

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Discrimination between Circulating Endothelial Cells and Blood Cell Populations with Overlapping Phenotype Reveals Distinct Regulation and Predictive Potential in Cancer Therapy

Neoplasia ◽

10.1593/neo.11916 ◽

2011 ◽

Vol 13 (10) ◽

pp. 980-990 ◽

Cited By ~ 13

Author(s):

Patrick Starlinger ◽

Philipp Brugger ◽

Christian Reiter ◽

Dominic Schauer ◽

Silvia Sommerfeldt ◽

...

Keyword(s):

Endothelial Cells ◽

Cancer Therapy ◽

Blood Cell ◽

Circulating Endothelial Cells ◽

Cell Populations

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Panax Quinquefolium L. Inhibits Thrombin-Induced Endothelin Release In Vitro

The American Journal of Chinese Medicine ◽

10.1142/s0192415x99000379 ◽

1999 ◽

Vol 27 (03n04) ◽

pp. 331-338 ◽

Cited By ~ 12

Author(s):

Chun-Su Yuan ◽

Anoja S. Attele ◽

Ji An Wu ◽

Tasha K. Lowell ◽

Zhenlun Gu ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Injury ◽

Vascular Endothelial Cells ◽

Cell Damage ◽

Umbilical Vein ◽

American Ginseng ◽

Protective Effects ◽

Panax Quinquefolium

Endothelial cell damage is considered to be the initial step in the genesis of thrombosis and arteriosclerosis, the common precursors of cardiovascular disorders. In this study, we evaluated the protective effects of American ginseng or Panax quinquefolium L. extracts on endothelial cell injury, and investigated effects of ginseng extracts on thrombin-induced endothelin release using cultured human umbilical vein endothelial cells. We observed that when endothelial cells pretreated with 1, 10, and 100 μg/ml of Panax quinquefolium L. extracts were incubated for 4 and 24 hr with thrombin, the concentration of endothelin was significantly decreased in a concentration dependent, time related manner (at 4 hr, IC50 = 5.1 μg/ml; at 24 hr, IC50 = 6.2 μg/ml). We further evaluated the effects of NG-nitro-L-arginine (NLA), a nitric oxide (NO) synthetase inhibitor, on the activity of Panax quinquefolium L. extracts. Following pretreatment of cultured endothelial cells with NLA, the inhibition of thrombin-induced endothelin release by Panax quinquefolium L. was significantly reduced (P < 0.05). This result suggests that the pharmacological action of Panax quinquefolium L. is, at least partially, due to NO release. Our data demonstrate that American ginseng may play a therapeutic role in facilitating the hemodynamic balance of vascular endothelial cells.

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Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.782841 ◽

2021 ◽

Vol 9 ◽

Author(s):

Irfan Khan ◽

Marcel O. Schmidt ◽

Bhaskar Kallakury ◽

Sidharth Jain ◽

Shaunt Mehdikhani ◽

...

Keyword(s):

Endothelial Cells ◽

Angiotensin Ii ◽

Cellular Senescence ◽

Low Dose ◽

Immune Cell ◽

Cell Damage ◽

Angiopoietin 2 ◽

Von Willebrand ◽

Willebrand Factor

Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a–Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a -dependent senescent cells by administration of AP20187. Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen and brain tissues. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects.

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High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage

Blood ◽

10.1182/blood-2007-03-078881 ◽

2007 ◽

Vol 110 (6) ◽

pp. 1857-1863 ◽

Cited By ~ 35

Author(s):

Cynthia A. Bolovan-Fritts ◽

Rodney N. Trout ◽

Stephen A. Spector

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Endothelial Cell ◽

T Cell ◽

Human Cytomegalovirus ◽

Cell Response ◽

Cell Injury ◽

Cell Damage ◽

Endothelial Damage ◽

T Cell Response

Abstract Human cytomegalovirus (CMV) infection has been linked to inflammatory diseases that involve vascular endothelial damage, including vascular disease and chronic transplant rejection. We previously reported that the host CD4+ T-cell response to CMV antigen presented by endothelial cells can produce interferon-γ and tumor necrosis factor-α at levels sufficient to drive induction of fractalkine, a key marker of inflammation, in endothelial cells. In this work, we report that donors with high frequencies of antigen-specific T cells to CMV (high responders) induce higher levels of activation-associated chemokines such as fractalkine, RANTES (regulated on activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1β, together with cell-adhesion markers in endothelial cells compared with donors with low levels of CMV-specific T cells (low responders). High-responder cultures had higher levels of leukocyte recruitment and adherence to the endothelial monolayers associated with progressive damage and loss of the endothelial cells. These processes that led to endothelial destruction only required viral antigen and did not require infectious virus. Our findings further support that CMV may represent one member of a class of persistent pathogens in which a high antigen-specific T-cell response defines an important risk factor for development of chronic inflammation and endothelial cell injury.

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Circulating endothelial cells – a super-sensitive marker of myocardial cell injury

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0029-1246888 ◽

2010 ◽

Vol 58 (S 01) ◽

Author(s):

K Neef ◽

YH Choi ◽

A Pierick ◽

JM Pyun ◽

O Liakopoulos ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Injury ◽

Myocardial Cell ◽

Circulating Endothelial Cells ◽

Myocardial Cell Injury ◽

Sensitive Marker

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Rapid Isolation of Human Endothelial Cells from Whole Blood Using S-Endo1 Monoclonal Antibody Coupled to Immuno-Magnetic Beads: Demonstration of Endothelial Injury after Angioplasty

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648397 ◽

1992 ◽

Vol 67 (01) ◽

pp. 147-153 ◽

Cited By ~ 89

Author(s):

F George ◽

C Brisson ◽

P Poncelet ◽

J C Laurent ◽

O Massot ◽

...

Keyword(s):

Monoclonal Antibody ◽

Endothelial Cells ◽

Endothelial Cell ◽

Whole Blood ◽

Magnetic Beads ◽

Cell Injury ◽

Circulating Endothelial Cells ◽

Heart Catheterization ◽

Human Endothelial Cells ◽

Blood Samples

SummaryThe presence in whole blood of circulating endothelial cells (EC) has been a subject of debate for many years. It could represent a good marker of vessel injury. We demonstrate here that human endothelial cells can be directly isolated and identified in circulating blood by means of an endothelial cell specific monoclonal antibody, S-Endol, coupled to micromagnetic beads. The specificity and efficacy of the assay were established using normal blood samples with cultured EC added. Specific rosettes formed between EC and beads could subsequently be isolated with a magnet. The rosetted cells were recovered with a yield >80%. Their endothelial origin was confirmed by the positive labelling of von Willebrand factor and thrombomodulin, as well as the presence of Weibel-Palade bodies. We applied this method to demonstrate significantly increased levels of EC in venous and arterial human blood samples in patients undergoing heart catheterization. This new whole blood immuno-separation method may be useful in determining endothelial cell injury in vascular disorders.

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