Vascular mechanisms of post-COVID-19 conditions: rho-kinase is a novel target for therapy

Sykes, R. A. et al. (2023) Vascular mechanisms of post-COVID-19 conditions: rho-kinase is a novel target for therapy. European Heart Journal - Cardiovascular Pharmacotherapy, 9(4), pp. 371-386. (doi: 10.1093/ehjcvp/pvad025) (PMID:37019821) (PMCID:PMC10236521)

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Background: In post-COVID-19 conditions (Long COVID), systemic vascular dysfunction is implicated but the mechanisms are uncertain, and treatment is imprecise. Methods: Patients convalescing after hospitalisation for COVID-19 and risk-factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated. Results: Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) three months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (p = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (p < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries (Masson's Trichrome (MT) 69.7% [95%CI: 67.8, 71.7]; picrosirius red 68.6% [95% CI: 64.4, 72.8]) versus controls (MT 64.9% [95%CI:59.4, 70.3] [p = 0.028]; picrosirius red 60.1% [95% CI: 55.4, 64.8], [p = 0.029]). Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9, 49.3) vs. controls (10.0%; 95% CI: 4.4, 15.6) (p < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated. Conclusion: Patients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Kamdar, Anna and McConnachie, Professor Alex and Jamieson, Dr Nigel and McIntosh, Dr Alasdair and Caputo, Ms Ilaria and Alves Moreira Lopes, Dr Rheure and Leslie, Ms Holly and Mangion, Dr Kenneth and Wood, Dr Colin and Montezano, Dr Augusto and Morrow, Dr Andrew and Touyz, Professor Rhian and Neves, Dr Karla and Berry, Professor Colin and McAbney, Mr John and McFarlane, Dr Richard and legrini, assya and Sykes, Dr Robert
Authors: Sykes, R. A., Neves, K. B., Alves-Lopes, R., Caputo, I., Jamieson, N. B., Kamdar, A., Legrini, A., Leslie, H., McIntosh, A., McConnachie, A., Morrow, A., McFarlane, R. W., Mangion, K., McAbney, J., Montezano, A. C., Touyz, R. M., Wood, C., and Berry, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:European Heart Journal - Cardiovascular Pharmacotherapy
Publisher:Oxford University Press
ISSN (Online):2055-6845
Published Online:05 April 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in European Heart Journal - Cardiovascular Pharmacotherapy 9(4):371-386
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301454CORonary MICrovascular Angina (CorMicA): a pilot trial with a nested MRI sub-studyColin BerryBritish Heart Foundation (BHF)PG/17/25/32884CAMS - Cardiovascular Science
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science
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312029Wellcome ISSF COVID Response FundKenneth MangionWellcome Trust (WELLCOTR)N/ACAMS - Cardiovascular Science
301364COMBINATION THERAPIES TARGETING IMMUNE EVASION IN PANCREATIC CANCERNigel JamiesonCancer Research UK (CRUK)C55370/A25813CS -Translational Research Centre