SARS-CoV-2 infection leads to cardiac pericyte loss, fibrosis, cardiomyocyte hypertrophy, and diastolic dysfunction

Jones, E.; Daems, M; Liesenborghs, Laurens; Cuijpers, Ilona; Boudewijns, Robbert; Raman, Jaishankar; Simmonds, Steven J.; Geuens, N; M, Lox; Verhamme, Peter; Sv, Linthout; Heymans, Stéphane; Tschoepe, C.; Neyts, Johan

doi:10.21203/rs.3.rs-105963/v1

Cited by 4 publications

(5 citation statements)

References 42 publications

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“…Under normal conditions, PCs act as stationary cells that interact with ECs to preserve vascular stability. PC detachment and migration from underlying vessels occurs in response to stress and may be responsible for the reduced PC coverage reported in the heart and lung microvasculature of COVID-19 patients [ 16 , 17 ]. Therefore, we interrogated the S protein capacity to trigger PC motility.…”

Section: Resultsmentioning

confidence: 99%

“…PC detachment and migration from underlying vessels occurs in response to stress and may be responsible for the reduced PC coverage reported in the heart and lung microvasculature of COVID-19 patients. (16,17) Therefore, we interrogated the S protein capacity to trigger PC motility. Using a wound closure assay with increasing amounts of S protein, we showed a dosage of 1000 ng/mL (corresponding to 5.8 nM) induced an increase in PC migration compared with vehicle (P<0.01) (Figure 5B&C).…”

Section: The Sars-cov-2 S Protein Interacts With and Causes Dysfunction Of Cardiac Pcmentioning

confidence: 99%

“…(13)(14)(15) Interestingly, a reduction in the vascular coverage by PCs was documented in the heart and lungs of human patients with COVID-19, in the absence of capillary rarefaction, suggesting that SARS-CoV-2 may affect the microvasculature by specifically targeting PCs. (16,17) The biological effects of SARS-CoV-2 are governed by the interaction of the homotrimeric spike (S) glycoprotein with cognate receptors on human cells. Such binding triggers a cascade of events that leads to fusion of the viral and cellular membranes to facilitate virus entry, (18) and subsequent manipulation of the host gene transcription machinery to regulate viral replication.…”

Section: Introductionmentioning

confidence: 99%

“…Cardiac myocytes and fibroblasts express the main entry receptor angiotensin-converting enzyme 2 (ACE2), but pericytes (PCs), mural cells that support the maintenance and repair of microvasculature throughout the myocardium [ 10–12 ], appear particularly susceptible because they reportedly express the highest levels of ACE2 in the heart [ 13–15 ]. Interestingly, a reduction in the vascular coverage by PCs was documented in the heart and lungs of human patients with COVID-19, in the absence of capillary rarefaction, suggesting that SARS-CoV-2 may affect the microvasculature by specifically targeting PCs [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2021

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wild type strain or the Alpha and Delta variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.

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Section: Resultsmentioning

confidence: 99%

Section: The Sars-cov-2 S Protein Interacts With and Causes Dysfunction Of Cardiac Pcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2021

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“…In the heart and lungs of COVID-19 patients, vascular coverage by pericytes is strongly decreased compared to healthy individuals without decreased capillary density, indicating that SARS-CoV-2 may negatively impact the microvasculature by preferentially targeting pericytes [20,21].…”

Section: Introduction-abnormal Vasculature In Sars-cov-2-associated L...mentioning

confidence: 99%

Sphingosine-1-Phosphate as Lung and Cardiac Vasculature Protecting Agent in SARS-CoV-2 Infection

Karam,

Auclair

2023

IJMS

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause severe respiratory illness with high mortality. SARS-CoV-2 infection results in a massive inflammatory cell infiltration into the infected lungs accompanied by excessive pro-inflammatory cytokine production. The lung histology of dead patients shows that some areas are severely emphysematous, with enormously dilated blood vessels and micro-thromboses. The inappropriate inflammatory response damaging the pulmonary interstitial arteriolar walls suggests that the respiratory distress may come in a large part from lung vasculature injuries. It has been recently observed that low plasmatic sphingosine-1-phosphate (S1P) is a marker of a worse prognosis of clinical outcome in severe coronavirus disease (COVID) patients. S1P is an angiogenic molecule displaying anti-inflammatory and anti-apoptotic properties, that promote intercellular interactions between endothelial cells and pericytes resulting in the stabilization of arteries and capillaries. In this context, it can be hypothesized that the benefit of a normal S1P level is due to its protective effect on lung vasculature functionality. This paper provides evidence supporting this concept, opening the way for the design of a pharmacological approach involving the use of an S1P lyase inhibitor to increase the S1P level that in turn will rescue the lung vasculature functionality.

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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

Avolio

Carrabba

Milligan

et al. 2020

Preprint

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BackgroundSevere coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses primarily the capsid spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known if the S protein alone, without the other viral elements, is able to trigger vascular cell signalling and provoke cell dysfunction.MethodsWe investigated the effects of the recombinant, stabilised S protein on primary human cardiac pericytes (PCs) signalling and function. Endpoints included cell viability, proliferation, migration, cooperation with endothelial cells (ECs) in angiogenesis assays, and release of pro-inflammatory cytokines. Adopting a blocking strategy against the S protein receptors ACE2 and CD147, we explored which receptor mediates the S protein signalling in PCs.FindingsWe show, for the first time, that the recombinant S protein alone elicits functional alterations in cardiac PCs. This was documented as: (1) increased migration, (2) reduced ability to support EC network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Furthermore, the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in cardiac PCs. Accordingly, the neutralization of CD147, using a blocking antibody, prevented the activation of ERK1/2 and partially rescued the PC function in the presence of the S protein.InterpretationOur findings suggest the new, intriguing hypothesis that the S protein may elicit vascular cell dysfunction, potentially amplifying, or perpetuating, the damage caused by the whole coronavirus. This mechanism may have clinical and therapeutic implication.FundingElizabeth Blackwell Institute (EBI) Rapid Response COVID-19 award.Research in contextEvidence before this studyThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses primarily the capsid spike (S) protein to engage with its receptors and infect host cells. Co-receptors and host cell proteases may also be involved. Angiotensin-converting enzyme 2 (ACE2) is the well-recognized entry receptor used by the virus in respiratory epithelial cells; it is also abundantly expressed in the human heart. Alongside ACE2, CD147 has recently emerged as a novel receptor for SARS-CoV-2. Yet, it is not clear if SARS-CoV-2 triggers adverse responses in cardiac vascular mural cells. Likewise, no investigation was devoted to verifying if the recombinant S protein alone can mimic the whole virus signalling.Added value of this studyThis study provides the first evidence that the recombinant S protein alone, without the other viral elements, is capable of eliciting cellular signalling in human cardiac pericytes, thereby inducing cell dysfunction. In addition, this study proposes CD147 as the leading receptor mediating S protein signalling in cardiac pericytes.Implications of all the available evidenceThese reports imply that fragments of the S protein might be able to elicit vascular cell dysfunction. Blocking the CD147 receptor may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.

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SARS-CoV-2 infection leads to cardiac pericyte loss, fibrosis, cardiomyocyte hypertrophy, and diastolic dysfunction

Cited by 4 publications

References 42 publications

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

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

Sphingosine-1-Phosphate as Lung and Cardiac Vasculature Protecting Agent in SARS-CoV-2 Infection

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

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