SARS-CoV-2 cell entry receptor ACE2 mediated endothelial dysfunction leads to vascular thrombosis in COVID-19 patients

Abstract

Several studies have described unusually high incidence of vascular thrombosis in coronavirus disease-2019 (COVID-19) patients. Pathogenesis of the vascular thrombosis in COVID-19 is least understood for now and presents a challenge to the treating physicians. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen for COVID-19, has been shown to bind to angiotensin converting enzyme 2 (ACE2) protein in human epithelial cells which facilitates its entry in the organ and mediate tissue specific pathogenesis. For ACE2 mediated cell entry of the SARS-CoV-2, co-expression of one more protein—Transmembrane protease serine 2 (TMPRSS2) is essential. Existing studies suggested significant expression of ACE2 and TMPRSS2 in human vascular endothelium. Vascular endothelial dysfunction can potentially activate coagulation cascade eventually resulting in thrombosis. ACE2 has proven role in the maintenance of endothelial integrity inside the vessels. Existing in situ evidence for SARS-CoV-1 (the causative agent for SARS pandemic of 2002, which shared ACE2 as cell entry receptor) suggested that virus binding can downregulate ACE2, thus can induce endothelial dysfunction. Recently, in situ evidence has been presented that SARS-CoV-2 can infect cells in engineered human vascular endothelium, which can be effectively blocked by using clinical-grade recombinant human ACE2. Based on the circumstantial evidence present in the literature, we propose a SARS-CoV-2 cell entry receptor ACE2 based mechanism for vascular thrombosis in COVID-19 patients.

The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

“…Since ACE2 is an analogue of ACE, which is a key regulator of the RAS system regulating hemodynamic homeostasis in the body, a balanced ACE/ACE2 ratio is fundamental for maintenance of endothelial integrity in vessels [65]. On the contrary, dysregulation of this ratio could be associated with vascular thrombosis [66,67]. This hypothesis is confirmed by in vitro studies carried out on lung tissues infected with SARS-CoV.…”

Pathogenesis guided therapeutic management of COVID-19: an immunological perspective

“…Recently some studies have reported complement system mediation of clotting in COVID-19 patients. Whether there is any SARS-CoV-2 specific virulence factor involved in increased thrombosis is not clear yet, however many authors have proposed a SARS-CoV-2 cell entry receptor ACE2 based mediation of vascular thrombosis [67,68]. ACE2 is known to express in human vascular endothelium and it has a well-established role in hemostasis [3,67,68].…”

“…Whether there is any SARS-CoV-2 specific virulence factor involved in increased thrombosis is not clear yet, however many authors have proposed a SARS-CoV-2 cell entry receptor ACE2 based mediation of vascular thrombosis [67,68]. ACE2 is known to express in human vascular endothelium and it has a well-established role in hemostasis [3,67,68]. There is a plausibility that virus mediated downregulation of ACE2 signaling may induce prothrombosis [67,68], however, any concrete evidence in reference of COVID-19 is currently lacking in literature.…”

“…ACE2 is known to express in human vascular endothelium and it has a well-established role in hemostasis [3,67,68]. There is a plausibility that virus mediated downregulation of ACE2 signaling may induce prothrombosis [67,68], however, any concrete evidence in reference of COVID-19 is currently lacking in literature.…”

Closing the portal to SARS-CoV-2 cellular entry: May open newer avenues…

“…Amidst the wide range of challenges posed by COVID-19 associated thrombosis, the Kumar et al proposition of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) cellular entry based angiotensin converting enzyme 2 (ACE2) signalling alterations being at the cornerstone of endothelial dysfunction and vascular pro-thrombotic environment, can have potentially important therapeutic implications [1] , [2] . Taking account of their molecular level description, we wish to highlight a few points to substantiate the clinical perspective of the discussion.…”