Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Abstract

Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

Keywords: COVID-19; COVID-19 therapies; Coagulopathy; Complement system; Endothelial protection; Endotheliopathy.

Fig. 1

Endothelial damage in the crossroad of infection, inflammation, and immunity in COVID-19. SARS-CoV-2 infection causes an endotheliopathy associated with a state of hyperinflammation and dysregulated immunity, in which different factors are involved. Soluble factors secreted by cells and tissues to the circulation, such as cytokines, adhesion receptors, coagulation proteins, elements of the activated complement system, and products released from the degradation of the endothelial glycocalyx. Cellular response involves macrophages and leukocytes, and to a lesser extent platelets and potentially circulating microvesicles secreted from injured cells. Signaling mediators may play a role, with activation of transcription factors, engagement of inflammasome, and TLR4 overexpression, promoting further activation of proinflammatory mediators. TLR, Toll-like receptor; HS, heparan sulfate

Fig. 2

Therapeutic strategies to improve outcomes in COVID-19 patients may include molecules addressing different targets involved in the pathogenesis of the disease. The battery of therapeutic compounds include the following: antivirals (remdesivir, convalescent plasma), molecules with effects against the inflammatory pathways (corticosteroids, tocilizumab, baricitinib), anticoagulants (heparins, DOAC), complement inhibitors (eculizumab, anti-complement C3 antibodies), or compounds reducing endothelial damage (defibrotide, Ang-II pathway antagonists, ACE inhibitors)