Ying Gue, PhD

Kaneko N, Satta S, Komuro Y, Muthukrishnan SD, Kakarla V, Guo L, An J, Elahi F, Kornblum HI, Liebeskind DS, et al. Flow-Mediated Susceptibility and Molecular Response of Cerebral Endothelia to SARS-CoV-2 Infection. Stroke. 2020.

On March 11, 2020, the World Health Organisation (WHO) officially announced the Coronavirus Disease 2019 (COVID-19) as a pandemic. The outbreak originated in China, and. as of now, has over 3 million cases with over 200,000 deaths as a result. The disease is attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

As the SARS-CoV-2 enters the host cell by binding the spike (S) protein to angiotensin converting enzyme 2 (ACE2), there has been an increased interest in studying the effect of ACE2 and the virus. Observational studies have shown that conditions which result in reduced ACE2 tissue expression will have a more severe disease course, notably males, advanced age, and patients with hypertension. Apart from the respiratory sequalae associated with COVID-19 infection, severe disease is further complicated by thromboembolic phenomenon including stroke. However, the mechanism underlying cerebral endothelial and response to COVID-19 infection remains unclear.

In this article by Kaneko et al., utilizing ex vivo models of human brain endothelial tissues, the authors were able to establish firstly, expression of ACE2 by human brain endothelial cells is low; secondly, ACE2 expression is increased in the presence of shear stress which facilitates binding of S protein of SARS-COV-2 to ACE2; and lastly, the binding triggers unique genes in human endothelial cells which are up-regulated to combat the infection.

This exciting study provides more information into the unknowns about the associations between regulation of ACE2 expression, S protein binding, and its subsequent response. Increase in ACE2 expression and facilitation of S protein binding in the presence of increased shear stress could provide the mechanistic insight of increased susceptibility of patients with cardiovascular disease, especially in the context of patients with atherosclerosis, to severe COVID-19 infection. Secondly, this study generates the hypothesis that this increase in tissue ACE2 expression could represent a biological protective mechanism against the prothrombotic phenomenon1 associated with higher shear within the vasculature and that this up-regulation could be blunted in patients with cardiovascular disease, hence, putting them more at risk of thrombotic complications.

The link between disease process, ACE2 expression, and serum ACE2 levels is unclear. Animal models have shown a reduction in ACE2 expression which appears to be associated with age; gender, i.e., males; and patients with cardiovascular (CV) risk factors including hypertension. A recently published study in the European Heart Journal has identified increased levels of serum ACE2 in patient populations who were associated with lower levels of tissue ACE2 expression.2 This was hypothesized to be due to a feedback mechanism, resulting in further decrease in membrane/tissue ACE2 expression.3 In patients with atherosclerotic disease, the increase in shear stress could initially increase expression of tissue ACE2 and, as the mechanism described, increase levels of serum ACE2, potentially resulting in a feedback downregulation of tissue ACE2 as identified from other animal models (Figure 1).

Regulation of ACE2 expression in healthy versus patients with established cardiovascular risk factors.
Figure 1: Regulation of ACE2 expression in healthy versus patients with established cardiovascular risk factors. As shown by Kaneko et al., increased shear stress results in an increase in tissue ACE2 expression. This resultant increase in tissue ACE2 leads to an increase in serum ACE2 (through ADAM-17 mediated shedding). This hypothetical increase in serum ACE2 causes a feedback loop, resulting in a downregulation of ACE2 expression, leading to the overall reduction in tissue expression of ACE2. When these individuals are exposed to SARS-COV-2 infection, due to the downregulation of ACE2 from raised serum ACE2, they are unable to oppose the deleterious cardiovascular complications associated with reduced tissue ACE2, putting them at higher risk of adverse complications.

One potential limitation is that the tissues studied would be much younger (aged 5 to 19 years) and healthier and may not reflect the risk seen in the typical CV risk population. It would be interesting to see if a similar response would be evident in patients with traditional CV risk factors. Secondly, this study utilizes brain endothelial tissues, and whether this effect could be extrapolated remains unknown. Lastly, the in vivo effect may be different from the laboratory study with the influence of other cellular pathways not explored.

Despite this, this study provides invaluable insight into the relationship between ACE2 expression and flow-mediated regulation, which could play an important role in the severity of COVID-19 infection.


1. Gue YX, Gorog DA. Reduction in ACE2 may mediate the prothrombotic phenotype in COVID-19. Eur Heart J. 2020;41:3198-3199.

2. Wallentin L, Lindbäck J, Eriksson N, et al. Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation. European Heart Journal. 2020.

3. Sama IE, Voors AA, van Veldhuisen DJ. New data on soluble ACE2 in patients with atrial fibrillation reveal potential value for treatment of patients with COVID-19 and cardiovascular disease. European Heart Journal. 2020.