Endothelial Dysfunction in COVID-19 Pathogenesis

SARS-CoV-2 infection extends beyond the respiratory epithelium to target the vascular endothelium through ACE2 binding. This leads to activation of endothelial cells, disruption of barrier function and initiation of endotheliitis. Infected or inflamed endothelium secretes pro-inflammatory cytokines and expresses adhesion molecules, recruiting leukocytes and amplifying the cytokine storm. Complement activation and neutrophil extracellular trap formation (NETosis) further degrade the glycocalyx and promote microthrombosis. Microvascular rarefaction, capillary leak and increased vascular permeability contribute to multiorgan dysfunction, including acute respiratory distress syndrome, acute kidney injury and neurological sequelae. Coagulopathy is fuelled by imbalance between tissue plasminogen activator and its inhibitors, elevated von Willebrand factor levels and dysregulated platelet–endothelial interactions. Persisting endothelial perturbation may underpin long-COVID through sustained immune activation, vascular inflammation and remodelling. Therapeutic strategies aim to restore endothelial quiescence, including ACE inhibitors, statins, antithrombotics and targeted anti-cytokine therapies against interleukin-6 or complement components. Emerging data suggest that modulation of mechanosensitive ion channels and inhibition of regulated cell death pathways may also protect microvascular integrity. Understanding these interconnected processes offers potential for improving outcomes in both acute and chronic stages of COVID-19.

Research from Nature Portfolio

Recent work has revealed a direct mechanistic link between viral protease activity and cerebral microvascular damage. The main protease (Mpro) of SARS-CoV-2 was shown to cleave NEMO, an essential regulator of NF-κB, in brain endothelial cells. This cleavage triggers endothelial cell death, capillary loss and blood–brain barrier disruption, evidenced by formation of acellular “string vessels”. Genetic ablation of receptor-interacting protein kinase 3 (RIPK3) or pharmacological inhibition of RIPK signalling preserved endothelial integrity, highlighting regulated cell death pathways as therapeutic targets for preventing neurological complications of COVID-19.

Research from all publishers

A study examining the spike protein receptor-binding domain (S-RBD) demonstrated that S-RBD binding to ACE2 in pulmonary arterial endothelial cells induces acute and sustained elevations of intracellular calcium via TRPV4, Piezo1 and store-operated channels. This calcium overload drives endothelial apoptosis and microvascular injury, which can be abrogated by channel blockade or by agents disrupting the ACE2–Piezo1-SOCC axis. Insights into variant-specific effects suggest reduced endothelial toxicity from Omicron S-RBD compared to the prototypic strain. A parallel focus on COVID-19 with diabetes mellitus has detailed how pre-existing endothelial dysfunction exacerbates hypercoagulability. Drivers such as NF-κB/NLRP3 inflammasome activation, cytokine storm, NETosis and complement engagement skew the balance of coagulation mediators towards thrombosis and hypofibrinolysis. Therapeutic avenues include specific inhibitors of thrombin, factor X, complement components or NETosis, alongside antidiabetic agents, to mitigate endotheliopathy in patients with metabolic comorbidity.

Endothelial Dysfunction in COVID-19 Pathogenesis publication trend

The graph below shows the total number of articles in endothelial dysfunction in covid-19 pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

ACE2: Cell-surface receptor (angiotensin-converting enzyme 2) that mediates viral entry into endothelial cells.

Endothelial dysfunction: Impaired endothelium-mediated regulation of vascular tone, permeability and haemostasis.

Endotheliitis: Inflammation of the endothelial lining leading to cellular activation and injury.

Cytokine storm: Excessive systemic release of pro-inflammatory cytokines causing widespread tissue damage.

NLRP3 inflammasome: A multiprotein complex that activates inflammatory caspases and induces interleukin-1β maturation.

NETosis: Programmed release of neutrophil extracellular traps composed of DNA and proteases.

Glycocalyx: Carbohydrate-rich layer on the endothelial surface essential for barrier function and mechanotransduction.

References

1. SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells. Signal Transduction and Targeted Therapy (2023).
2. Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus. Cardiovascular Diabetology (2024).
3. The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nature Neuroscience (2021).
4. Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. eLife (2021).
5. Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19?. Clinical Medicine (2020).