Skip to content

COVID-19 Spike Protein Impairs Endothelial Function

A newly published study utilizing an endothelial function model has presented a thorough understanding of the histopathological consequences caused by the impairment of ACE2 through downregulation by the SARS-CoV-2 spike protein.


Coronavirus Disease 2019 (COVID-19) infects host cells through the binding of the spike (S) glycoprotein of the SARS-CoV-2 to ACE2 (angiotensin-converting enzyme 2). Infection of vascular endothelium with SARS-CoV-2 elicits a glycolytic shift and results in reactive oxygen species production in the mitochondria. ACE2 is localized in the lungs, gastrointestinal tract, nasal mucosa, heart, kidneys, and liver. Therefore, multiple organ vasculitis and inflammation can be produced by SARS-CoV-2. More importantly, factors such as age, co-morbidities (hypertension, diabetes, blood clotting disorders, obesity) among others, are risk factors in COVID-19 patients that lead to cardiovascular complications in addition to respiratory disease.

In this paper, the authors showed that the SARS-CoV-2 spike protein decreased levels of ACE2 in lungs, impaired mitochondrial function, and ultimately destabilized ACE2.

  • Syrian hamsters challenged with a non-infectious pseudovirus-expressing S protein showed thickening of the alveolar septa and increased infiltration of mononuclear cells.
  • Confocal images of human arterial endothelial cells (ECs) treated with the S protein revealed mitochondrial fragmentation, suggesting an alteration in mitochondrial dynamics.
  • In vitro oxygen consumption and extracellular acidification rate assays found that dephospho-mimetic ACE2 reduced basal mitochondrial respiration and ATP production in ECs.
  • In vivo acetylcholine- and sodium nitroprusside-induced vasodilation experiments showed that vasodilation is hindered in pulmonary arteries by dephospho-mimetic ACE2.
  • Western blots showed downregulation of the pACE2Ser480/ACE2 expression in infected hamster lung tissue and in human arterial ECs.



Authors hypothesised that ACE2 reduction might decrease SARS-CoV-2 virus infectivity, thereby protecting endothelium. However, ACE2 reduction led to dysfunctional endothelium because ACE2 is protective in the cardiovascular system. The work from Lei Y and colleagues published this year in Circulation Research illuminates key steps in the mechanism by which SARS-CoV-2 leads to vascular damage. These findings suggested that vaccination not only protects from infection but also inhibits endothelial damage in patients with COVID-19.



Epistem is a GCLP-accredited laboratory specialising in providing biomarker, target discovery and personalised medicine information. We offer microarray, qPCR and NGS services (including the 10X genomics platform for single-cell sequencing) for gene expression, whole-genome, and epigenetic analysis in all species.

The Histology and Immunohistochemistry team at Epistem have a wealth of experience in developing IHC protocols for a range of biological targets. Our deep understanding of IHC methodology has allowed us to develop and troubleshoot hundreds of working protocols for both automated (Ventana Discovery Ultra) and manual applications. We offer a bespoke service which can be suited to your project. We can work readily with FFPE, frozen tissues, with chromogenic and fluorescent detection systems as well as RNAScope methodologies.

Dr. Fernando Magdaleno Verduzco has recently joined Epistem to lead our fibrosis development programme, which includes liver, lung, and kidney models. We would be happy to talk to you about any fibrosis-related enquiries you have.