CE14 - Physiologie et physiopathologie

Endothelial damage and repair in SARS-CoV-2 related vascular injury – ENDOCOV-19

Submission summary

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can present with a range of manifestations. SARS-CoV-2 infects type II pneumocytes by binding to membrane-bound angiotensin-converting enzyme 2 (ACE2). Rapidly after the outbreak, reports showed that COVID-19 affects other organs than the lungs, due to the tropism of SARS-CoV-2 for ACE2-expressing cells, mainly endothelial cells (EC) of both small and large arteries and veins. Macro-thrombotic events became a signature of the disease and associated with poor prognosis. In Paris University Hospitals, during the COVID-19 peak in March 2020, > 50 patients presented major acute thrombosis of the aorta and the lower limb arteries. Moreover, limited postmortem evaluation of COVID-19 patients observed severe multi-organ endotheliitis associated with endothelial cellular death, and the presence of viral elements within EC. Direct viral infection of the endothelium, diffuse endothelial inflammation and widespread thrombosis was observed in lungs of COVID-19-deceased patients. Altogether, these observations strongly implicate the vascular endothelium in the pathogenesis of severe COVID-19. Available information derived from limited data and observational studies emphasize the predominant role of endothelial dysfunction in patients with COVID-19. Yet the cellular and molecular impact of COVID-19 on the vasculature remains largely unknown.

We propose here to combine the expertise of three teams recognized in the field of vascular disease and endothelial (dys)function in order to describe the patterns of vascular damage observed in small, middle-size, and large arteries upon SARS-CoV-2 infection, in comparison with influenza virus infection, by combining morphological, cellular, molecular and lineage-specific genetic studies in murine preclinical model and human samples. We have generated a conditional hACE2 knock-in into the murine ACE2 gene (CKI-hACE2) to allow conditional cell type-specific expression of hACE2, in particular in specific vascular cell population using already available in the lab Cdh5-CreERT2 and NG2-CreERT2 mouse line. The resulting humanized mice will be intranasally infected. Second, we obtained the authorization of the French Biomedicine Agency (Agence de la Biomédecine) to perform human arterial and adjacent muscle biopsies in twelve COVID-19 deceased patients in Intensive Care Units of Henri Mondor Hospital.

Specifically, we will implement the following program:

Aim 1 To provide a comprehensive staged analysis of the vascular morphological changes related to SARS-CoV-2 infection, based on histology, immuno-histochemistry, and standard and advanced post-mortem and intravital imaging techniques, and the in vivo and in vitro testing of the endothelial function. Extensive molecular analysis of vessels exposed to SARS-CoV-2 will determine the molecular signature of the infection.
Aim 2. To investigate the cell-specific role of EC and/or pericytes in the vessel wall upon viral infection and alteration, using staged morphometric analysis in both mouse models and human samples as well as in vivo and in vitro investigation
Aim 3 To describe the status of endothelial protective factors in the setting of the infection. We will focus our analysis on the glycocalyx, the Desert Hedgehog (DHh) factor, a downstream effector of Klf2, which we demonstrated endothelial healing properties in ischemic pathologies, and the nitric oxide signaling.
Aim 4 Serine protease inhibitors have been deductively suggested as therapeutic candidates since they inhibit TMPRSS2 and thus abrogate the proteolytic processing of virus. As for Dhh agonists in Aim 3, we propose to test these candidates on the novel humanized mouse.

This program will provide the first comprehensive analysis of the cellular and molecular functions of the vascular bed endothelium, and its protective armamentarium during the SARS-CoV-2 infection

Project coordination

Joseph Touma (Université Paris-Est Créteil)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Inserm UMR1034 Biologie des maladies cardiovasculaires Institut National de la Santé et de la Recherche Médicale
UPEC Université Paris-Est Créteil

Help of the ANR 474,880 euros
Beginning and duration of the scientific project: January 2022 - 48 Months

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