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. 2024 Jun 27;16(4):561-571.
doi: 10.3390/idr16040042.

Persistent Vascular Complications in Long COVID: The Role of ACE2 Deactivation, Microclots, and Uniform Fibrosis

Christina-Michailia Sideratou  1 , Christos Papaneophytou  1
Affiliations

Persistent Vascular Complications in Long COVID: The Role of ACE2 Deactivation, Microclots, and Uniform Fibrosis

Christina-Michailia Sideratou et al. Infect Dis Rep. .

Abstract

Angiotensin-converting enzyme 2 (ACE2), a key regulator in vasoregulation and the renin-angiotensin system, is hypothesized to be downregulated in patients with COVID-19, leading to a cascade of cardiovascular complications. This deactivation potentially results in increased blood pressure and vessel injury, contributing to the formation and persistence of microclots in the circulation. Herein, we propose a hypothesis regarding the prolonged vascular complications observed in long COVID, focusing on the role of ACE2 deactivation and/or shedding, the persistence of microclots, and the unique pattern of fibrosis induced by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Furthermore, we propose that the distinctive, uniform fibrosis associated with COVID-19, which is challenging to detect through conventional X-ray imaging, exacerbates vascular injury and impairs oxygenation. The persistence of these microclots and the unique fibrosis pattern are suggested as key factors in the extended duration of vascular complications post-COVID-19 infection, regardless of the initial disease severity. Moreover, plasma ACE2 activity has the potential to serve as prognostic or diagnostic biomarkers for monitoring disease severity and managing long COVID symptoms. Elucidating the role of ACE2 deactivation and the consequent events is vital for understanding the long-term effects of COVID-19. The experimental verification of this hypothesis through in vitro studies, clinical longitudinal studies, and advanced imaging techniques could yield significant insights into the pathophysiological mechanisms underlying long COVID, thereby improving the management of patients, particularly those with cardiovascular complications.

Keywords: ACE2; RAS; fibrosis; long COVID; microclots; severe acute respiratory syndrome-coronavirus-2; vasoregulation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A graphical representation of the proposed hypothesis. (A) Normal function of ACE2 in the renin–angiotensin system (RAS): Renin converts angiotensinogen to angiotensin I (Ang I). Ang I is then converted to angiotensin II (Ang II) by ACE, which is present on the surfaces of endothelial cells, primarily in the lungs and kidneys. ACE2 acts as a counter-regulator by converting Ang II to angiotensin 1–7 (Ang-(1–7)), which exhibits vasodilatory and anti-inflammatory activities, thus regulating blood pressure. (B) Impact of SARS-CoV-2 on ACE2 leading to long COVID: SARS-CoV-2 binds to ACE2, reducing its presence on the endothelium of the lung and other organs, which disrupts the normal function of ACE2. This increases Ang II levels, leading to vasoconstriction, vessel injury, and inflammation. Moreover, the binding of SARS-CoV-2 to ACE2 causes the shedding of these receptors by various proteases, leading to elevated levels of plasma ACE2. These events contribute to the formation of persistent microclots and uniform fibrosis, leading to impaired oxygenation—a hallmark symptom of long COVID that affects various systems, including the respiratory (RS), central nervous (CNS), and cardiovascular (CVS) systems (created with BioRender.com, accessed on 1 April 2024).
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