Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting.

Keywords: COVID-19; arginine; chronic disease; chronic obstructive pulmonary disease; endothelial function; exercise; heart failure; occupational medicine; outcome; rehabilitation.

Figure 1

Flow-mediated dilation (FMD) assessment using a Food and Drug Administration (FDA)-cleared software for automatic edge detection (Panel (A)), wall tracking (Panel (B)), and shear-rate monitoring (Panel (C)). Reproduced with permission from Quipu SRL, Pisa, Italy.

Figure 2

Physiopathology of endothelial dysfunction in coronavirus disease 2019 (COVID-19). SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TNF-α: tumor necrosis factor alpha; ADAM17: a disintegrin and metalloprotease 17; ACE2: angiotensin-converting enzyme 2; Ang II: angiotensin II; Ang 1-7: angiotensin_1-7; AT1: angiotensin receptor type 1; AT4: angiotensin receptor type 4; Gα_12/13: guanine nucleotide-binding protein alpha 12/13; RhoA: Ras homolog family member A; ROCK: Rho-associated protein kinase; p38 MAPK: p38 mitogen-activated protein kinase; NO: nitric oxide; IL-1: interleukin-1; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; VCAM-1: vascular cell adhesion molecule-1; ICAM-1: intercellular adhesion molecule-1; PSGL-1: P-selectin glycoprotein ligand-1; VLA-4: very late antigen-4 integrin; LFA-1: lymphocyte function-associated antigen-1 integrin.