Molecular Mechanisms of Endothelialitis in SARS-CoV-2 Infection: Evidence for VE-Cadherin Cleavage by ACE2

• Published in: International journal of molecular sciences 2023-08, Vol.24 (15), p.12525
• Main Authors: Bouillet, Laurence, Deroux, Alban, Benmarce, Meryem, Guérin, Chloé, Bouvet, Laura, Garnier, Olivia, Martin, Donald K, Vilgrain, Isabelle
• Format: Article
• Language: English
• Subjects: ACE2; Adhesives; Amino acids; Analysis; Angiotensin-Converting Enzyme 2 - metabolism; Antibodies; Blood circulation disorders; Blood vessels; Bond strength; Cadherins - metabolism; Cloning; COVID-19; COVID-19 - metabolism; Cytokines; Disease transmission; Endothelial Cells - metabolism; endothelium; Endothelium, Vascular - metabolism; Enzymes; Health aspects; Humans; Infections; Kinases; Life Sciences; Long COVID; long COVID syndrome; Pathogenesis; Patients; Peptides; Phosphorylation; Plasma; Post-Acute COVID-19 Syndrome; Proteins; Pulmonary arteries; SARS-CoV-2 - metabolism; SARS-CoV-2 infection; Severe acute respiratory syndrome coronavirus 2; VE-cadherin; Viral antibodies
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241512525

Long COVID-19 syndrome appears after Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection with acute damage to microcapillaries, microthrombi, and endothelialitis. However, the mechanisms involved in these processes remain to be elucidated. All blood vessels are lined with a monolayer of endothelial cells called vascular endothelium, which provides a the major function is to prevent coagulation. A component of endothelial cell junctions is VE-cadherin, which is responsible for maintaining the integrity of the vessels through homophilic interactions of its Ca -dependent adhesive extracellular domain. Here we provide the first evidence that VE-cadherin is a target in vitro for ACE2 cleavage because its extracellular domain (hrVE-ED) contains two amino acid sequences for ACE2 substrate recognition at the positions P-F and PMKP- L. Indeed, incubation of hrVE-ED with the active ectopeptidase hrACE2 for 16 hrs in the presence of 10 μM ZnCl showed a dose-dependent (from 0.2 ng/μL to 2 ng/μL) decrease of the VE-cadherin immunoreactive band. In vivo, in the blood from patients having severe COVID-19 we detected a circulating form of ACE2 with an apparent molecular mass of 70 kDa, which was barely detectable in patients with mild COVID-19. Of importance, in the patients with severe COVID-19 disease, the presence of three soluble fragments of VE-cadherin (70, 62, 54 kDa) were detected using the antiEC1 antibody while only the 54 kDa fragment was present in patients with mild disease. Altogether, these data clearly support a role for ACE2 to cleave VE-cadherin, which leads to potential biomarkers of SARS-CoV-2 infection related with the vascular disease in "Long COVID-19".