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Vascular mechanisms of post-COVID-19 conditions: Rho-kinase is a novel target for therapy
Robert A Sykes1,2, Karla B Neves1,3, Rhéure Alves-Lopes1
1School of Cardiovascular and Metabolic Health, University of Glasgow, UK.
Insights
Long COVID patients exhibit increased vascular fibrosis and myosin light chain phosphorylation, indicating impaired blood vessel function. Rho-kinase activation is identified as a potential therapeutic target for these conditions.
Area of Science:
- Vascular Biology
- Immunology
- Pathophysiology
Background:
- Systemic vascular dysfunction is implicated in post-coronavirus disease-19 (post-COVID-19) conditions, also known as long COVID.
- The precise mechanisms underlying this dysfunction and effective treatment strategies remain uncertain.
Purpose of the Study:
- To investigate the mechanisms of vascular dysfunction in patients with long COVID.
- To identify potential therapeutic targets for post-COVID-19 conditions.
Main Methods:
- Multisystem phenotyping including blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy.
- Wire myography, histopathology, immunohistochemistry, and spatial transcriptomics of small resistance arteries.
- Assessment of vasorelaxation and vasoconstriction, with and without a RhoA/Rho-kinase inhibitor (fasudil).
Main Results:
- Arteries from COVID-19 patients showed increased vasoconstriction and reduced endothelium-independent vasorelaxation compared to controls.
- Fasudil abolished the observed differences in vasorelaxation.
- Histopathology revealed greater collagen abundance (vascular fibrosis) and increased phosphorylated myosin light chain staining in vascular smooth muscle cells of COVID-19 patients.
- Upregulated gene pathways associated with extracellular matrix alteration and viral mRNA replication were observed.
Conclusions:
- Patients with post-COVID-19 conditions exhibit enhanced vascular fibrosis and myosin light chain phosphorylation.
- Rho-kinase activation is a significant factor in the vascular dysfunction seen in long COVID.
- Rho-kinase activation represents a novel therapeutic target for clinical trials in post-COVID-19 conditions.
Background:
In post-coronavirus disease-19 (post-COVID-19) conditions (long COVID), systemic vascular dysfunction is implicated, but the mechanisms are uncertain, and the treatment is imprecise.
Methods And Results:
Patients convalescing after hospitalization 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. Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) 3 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% confidence interval (CI): 67.8-71.7]; picrosirius red 68.6% [95% CI: 64.4-72.8]} vs. 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.
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