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Cardiac microvascular pericytes in COVID-19 patients

A comment by the ESC WG on Coronary Pathophysiology & Microcirculation

Vascular Tone, Permeability, Microcirculation

Pericytes are a heterogeneous population of cells embedded in the microvascular basement membrane in direct contact with endothelial cells. Pericytes are important cell components for the formation, maintenance, and remodelling of capillaries (1), exerting critical regulatory functions in the microcirculation (2). Thus, pericytes undertake microvascular barrier functions and facilitate tissue's recruitment of immune cells in response to viral and bacterial proteins. Pericyte-dependent barrier control occurs both directly through close physical contact with endothelial cells and indirectly through paracrine signalling by modulating the phenotype of effector cells (3). During such immune responses, pericytes change phenotype to become migratory (4), possibly abandoning other functions of importance to capillary bed integrity, function, and repair. Emerging evidence demonstrates that cardiac pericytes can detach from the capillary and migrate into the perivascular interstitium to differentiate into myofibroblasts. This process leads to increased vascular permeability and inflammation, and it ultimately results in coronary fibrosis, perivascular fibrosis, and capillary rarefaction (5).

Microcirculation is well recognized as a component of the response to pathogens and microvascular dysfunction is a possible merging mechanism underlying the diverse cardiovascular complications and acute myocardial injury associate with greater disease severity and worse outcomes after SARS-CoV-2 infection (6). SARS-CoV-2 infects host cells via binding of viral Spike (S) protein to the transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). In this respect, cardiac pericytes abundantly express ACE2 (7,8). In addition, pericytes express proteases (e.g. cathepsin) to cleave S-protein, a required process for viral entry. To this respect, a recently published retrospective study on heart autopsy specimens from COVID19 patients suggested that SARS-CoV-2 associates with myocyte death and cardiac pathology due to a process that initiates by impeded capillary circulation in the absence of cellular infiltration by immune cells (9).  These findings, however, left unresolved the question of whether SARS-CoV-2 infects and damage microvascular pericytes in the heart, thereby altering their phenotype and function.

In the November issue of Clinical Science, Avolio et al.  (10) provide novel insights into the mechanisms used by SARS-CoV-2 to cause vascular damage. Using primary human cardiac pericytes and in vitro cell culture studies, authors evidenced that cardiac pericytes are rarely infected by SARS-CoV-2 (independently infectiveness potential of the variant type). This differs from other ACE2-rich cell types including the gut epithelial cells (Caco-2-ACE2 cell line) in which the virus enters the cells after the binding of the Spike-S protein to the cell receptors.

Interestingly, Avolilo et al. evidenced that a recombinant Spike (S)-protein, outside the context of infectious virus, elicits cellular signalling and functional alterations in cardiac pericytes affecting their role in maintaining the capillaries structure at the time of inducing a pro-inflammatory and pro-apoptotic background, thereby pointing to an alternative non-infectious damaging mechanism triggered by the S-protein in these cells in the heart. Protein-S mediated cell signalling had been previously evidenced in pulmonary vascular cells (11). However, in the present study, Avolio et al., using a specific blocking design against the S-protein receptors ACE2 and CD147 (Basigin or extracellular matrix metalloproteinase inducer -EMMPRIN-), demonstrated that CD147 receptor, and not ACE2, leads S-protein signalling in cardiac pericytes.

Based on the fact that high levels of S-Protein are consistently found in plasma of COVID-19 patients, Avolio et al. suggest SARS-CoV-2 S-protein to act expanding damage to different organs beyond virus infection by a signalling mechanism elicited through microvascular pericytes. However, findings reported by Avolio et al. should be interpreted with prudence as results just rely on cell culture in vitro models which might not reflect the response of microvascular pericytes in vivo. Yet, the reported data on isolated human primary pericytes merit further validation studies in in vivo models to support the translational relevance of SARS-CoV-2 Spike protein to elicit a pericyte-mediated non-infective mechanism of COVID-19 microvascular disease.


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  2. O'Farrell FM, Attwell D, A role for pericytes in coronary no-reflow, Nature reviews. Cardiology 2014; 11(7) 427-32
  3. Gaceb A, Paul G. Pericyte Secretome. Adv Exp Med Biol. 2018; 1109:139-163. doi: 10.1007/978-3-030-02601-1_114.- (Wang et al., 2012)
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  6. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, Madhur MS, Tomaszewski M, Maffia P, D'Acquisto F, Nicklin SA, Marian AJ, Nosalski R, Murray EC, Guzik B, Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, McInnes IB.. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020;116:1666–1687.
  7. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res. 2020; 116(6):1097-1100. doi: 10.1093/cvr/cvaa078.
  8. Nicin L, Wagner JUG, Luxán G, Dimmeler S. Fibroblast-mediated intercellular crosstalk in the healthy and diseased heart. FEBS Lett. 2021 Nov 17. doi: 10.1002/1873-3468.14234. Online ahead of print.
  9. Fremont-Smith M, Gherlone N, Smith N, Tisdall P, Ricke DO. Models for COVID-19 Early Cardiac Pathology Following SARS-CoV-2 Infection. Int J Infect Dis. 2021; 113:331-335. doi: 10.1016/j.ijid.2021.09.052.
  10. Avolio E, Carrabba M, Milligan R, Kavanagh Williamson M, Beltrami A, Gupta K, Elvers KT, Gamez M, Foster R, Gillespie K, Hamilton F, Arnold D, Berger I, Davidson A, Hill DJ, Caputo M, Madeddu P. The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease. Clin Sci (Lond). 2021; 22:CS20210735. doi: 10.1042/CS20210735.
  11. Suzuki YJ, Nikolaienko SI, Dibrova VA, Dibrova YV, Vasylyk VM, Novikov MY, Shults NV, Gychka SG. SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells. Vascul Pharmacol. 2021; 137:106823. doi: 10.1016/j.vph.2020.106823.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.