Pathophysiological mechanisms of COVID-19-related endothelial dysfunction and potential therapies

By Dr. Chinta SidharthanReviewed by Aimee MolineuxOct 19 2022

In a recent review published in Life, researchers discussed the pathophysiological mechanisms of endothelial dysfunction associated with severe coronavirus disease 2019 (COVID-19). They commented on the potential therapeutic strategies to treat endothelial damage and coagulopathy related to COVID-19.

Background

Emerging research shows that while severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily targets the pulmonary and respiratory systems, long-lasting health concerns associated with micro-thromboembolism, myocardial injury, myocarditis, and renal failure have been observed in COVID-19 patients. A growing body of evidence indicates that endothelial damage due to the viral infection and the inflammatory response during COVID-19 could contribute to the severity of the disease.

Endothelial cells regulate inflammation, coagulation, dilation of blood vessels, and oxidative stress. Studies have shown that vascular endothelial damage and dysfunction contribute significantly to severe pulmonary outcomes during COVID-19. Furthermore, many extrapulmonary COVID-19 symptoms have also been linked to endothelial dysfunction. Exploring the pathophysiology of endothelial damage and investigating potential treatment methods could help limit severe COVID-19 outcomes.

Endothelial dysfunction

The review reported the possible mechanisms that explain the SARS-CoV-2 tropism towards endothelial cells. Viral entry into the host cell begins with the binding of the SARS-CoV-2 spike protein to the angiotensin-converting enzyme-2 (ACE-2) receptor and downstream activation of the spike protein subunits. The ACE-2 enzyme modulates the renin-angiotensin-aldosterone system (RAAS) signaling pathway, which controls local and systemic blood flow and pressure.

Interactions of the spike protein with the nuclear factor κB pathway and integrin α5β1 are thought to cause endothelial damage. SARS-CoV-2 is also thought to alter the endothelial glycocalyx integrity and apoptosis of endothelial cells.

The authors also discussed the inflammation and hypercoagulability resulting from endothelial damage. Endothelial cells produce endogenous molecules such as prostaglandin and nitric oxide that are involved in controlling platelet aggregation and maintaining vascular homeostasis. Endothelial damage induces hypercoagulation and contractions of the vasculature, resulting in an increased risk of thromboembolic events. Hypercoagulation also reduces blood flow to other regions, such as the kidneys and myocardium, causing disseminated intravascular coagulation.

Severe COVID-19 is associated with extremely elevated levels of interleukins (IL) such as IL-1β, IL-10, IL-6, and IL-7, also known as “cytokine storm,” which increases tumor necrosis factor secretion and interferon-γ induced apoptosis. The elevated cytokines cause endothelial damage, which further increases the secretion of inflammatory molecules, causing a cyclic reaction.

Endothelial dysfunction and SARS-CoV-2 variants

The review investigated studies that compared the transmission, virulence, and immune evasion of SARS-CoV-2 variants of concern. The results indicated that while the Omicron variant had mutations in the spike protein and receptor binding domain that resulted in immune evasion and high transmission, it caused lower severity and did not affect the endothelial cells as much as the Delta variant. Studies found fewer incidences of pulmonary embolism associated with the Omicron variant.

Manifestations and mechanisms

The pulmonary manifestations range from mild to severe and vary according to comorbidities, age, sex, viral load, genetics, and ethnicity. The symptoms include upper respiratory tract infections to hypoxia, acute respiratory distress syndrome, and pulmonary edema.

Extrapulmonary manifestations can be seen in multiple organ systems, including the cardiac, renal, nervous, and gastrointestinal systems. Complications include arrhythmias, myocarditis, proteinuria, kidney failure, seizures, encephalopathy, cerebrovascular disease, intestinal inflammations, deep vein thrombosis, and many more.

Emerging research on “long COVID” have revealed that endothelial damage is one of the contributing factors to the chronic systemic concerns such as thrombosis, fatigue, cardiac complications such as myocardial hypertrophy, and neurodegenerative symptoms experienced by COVID-19 patients in the months following their recovery.

Therapeutic avenues

Data from clinical trials suggest various treatment strategies to target coagulopathy and endothelial damage caused by COVID-19. Low molecular weight heparin exhibits antiviral and anti-inflammatory activity in addition to its antithrombotic effects. Corticosteroids are generally used to treat the respiratory symptoms of SARS-CoV-2 infections. Additionally, corticosteroids exhibit anti-inflammatory activity and reduce pro-coagulation factors like fibrinogen and von Willebrand factor.

Although controversial because of their role in increasing ACE-2 receptor expression and potentially facilitating viral entry, RAAS inhibitors are also thought to reduce endothelial damage. The authors also presented a comprehensive summary of the studies that discuss the use of statins, antiviral agents, and monoclonal antibodies in addressing endothelial dysfunction and hypercoagulation.

Conclusions

To summarize, the review discussed the possible pathophysiological mechanisms of endothelial dysfunction that results from severe COVID-19 and causes immediate and long-term multi-organ damage. Endothelial dysfunction mostly manifests as hypercoagulation and inflammation, and the extent of endothelial damage varies based on the SARS-CoV-2 variant of concern.

The authors presented data from various clinical trials on the use of heparins, RAAS inhibitors, corticosteroids, monoclonal antibodies, and many more therapeutic options which could potentially be used to reduce the endothelial damage caused by severe SARS-CoV-2 infections.