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Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients

Liqun He, Maarja Andaloussi Mäe, Ying Sun, Lars Muhl, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Riikka Pietilä, Lei Zhang, Yuan Xie, Stefanos Leptidis, Guiseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsenen, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, Emil Hansson, Taija Mäkinen, Xiao-Rong Peng, Thomas D. Arnold, Kari Alitalo, Lars I Eriksson, Urban Lendahl, Christer Betsholtz
doi: https://doi.org/10.1101/2020.05.11.088500
Liqun He
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Maarja Andaloussi Mäe
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Ying Sun
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Lars Muhl
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Khayrun Nahar
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Elisa Vázquez Liébanas
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Malin Jonsson Fagerlund
3Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Solna and Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
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Anders Oldner
3Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Solna and Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
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Jianping Liu
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Guillem Genové
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Riikka Pietilä
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Lei Zhang
4Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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Yuan Xie
4Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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Stefanos Leptidis
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Guiseppe Mocci
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Simon Stritt
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Ahmed Osman
5Department of Women’s and Children’s Health, Karolinska Institutet, Solna, Sweden
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Andrey Anisimov
6Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland
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Karthik Amudhala Hemanthakumar
6Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland
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Markus Räsenen
6Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland
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Johan Björkegren
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
7Institute of Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, US
8Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
9Clinical Gene Networks AB, Stockholm, Sweden
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Michael Vanlandewijck
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Klas Blomgren
5Department of Women’s and Children’s Health, Karolinska Institutet, Solna, Sweden
10Cardiovascular, Renal and Metabolism (CVRM), IMED Biotech Unit, AstraZeneca BioPharmaceuticals R&D, Gothenburg, Sweden
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Emil Hansson
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
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Taija Mäkinen
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Xiao-Rong Peng
11Department of Pediatric oncology, Karolinska University Hospital, Stockholm, Sweden
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Thomas D. Arnold
12Department of Pediatrics, University of California San Francisco, USA
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Kari Alitalo
6Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland
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Lars I Eriksson
3Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Solna and Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
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Urban Lendahl
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
13Department of Cell and Molecular Biology, Karolinska Institutet, Sweden
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Christer Betsholtz
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden
14Department of Medicine Huddinge, Karolinska Institutet, Sweden
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  • For correspondence: christer.betsholtz@ki.se christer.betsholtz@igp.uu.se
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Abstract

Accumulating clinical observations suggest pathogenesis beyond viral pneumonia and its secondary consequences in COVID-19 patients. In particular, many patients develop profound hyperinflammation and hypercoagulopathy with disseminated thrombogenesis and thromboembolism, which we observe also in a Swedish COVID-19 intensive care patient cohort. To understand these vascular manifestations, it is important to establish the potential vascular entry point(s) of the SARS-CoV-2 virus, i.e. which vascular cell types express the SARS-CoV-2 receptor ACE2. We present data that ACE2 is specifically and highly expressed in microvascular pericytes, but absent from endothelial cells, perivascular macrophages and fibroblasts. Mice with pericyte ablation show increased expression and release of Von Willebrand Factor from microvascular endothelial cells, suggesting that pericytes orchestrate thrombogenic responses in neighboring endothelial cells. Identifying pericytes rather than endothelial cells as the ACE2-expressing cells in the vasculature may explain why hypertension, diabetes and obesity are risk factors for severe COVID-19 patients, as these conditions are characterized by an impaired endothelial barrier function, allowing SARS-CoV-2 to reach and infect the pericytes that are normally shielded from the blood behind an intact endothelial barrier. This novel COVID-19-pericyte hypothesis is testable, offers explanations for some of the most enigmatic and lethal aspects of COVID-19 and calls for further investigations into the possible benefits of preventive anticoagulant therapy.

Competing Interest Statement

The authors have declared no competing interest.

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Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients
Liqun He, Maarja Andaloussi Mäe, Ying Sun, Lars Muhl, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Riikka Pietilä, Lei Zhang, Yuan Xie, Stefanos Leptidis, Guiseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsenen, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, Emil Hansson, Taija Mäkinen, Xiao-Rong Peng, Thomas D. Arnold, Kari Alitalo, Lars I Eriksson, Urban Lendahl, Christer Betsholtz
bioRxiv 2020.05.11.088500; doi: https://doi.org/10.1101/2020.05.11.088500
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Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients
Liqun He, Maarja Andaloussi Mäe, Ying Sun, Lars Muhl, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Riikka Pietilä, Lei Zhang, Yuan Xie, Stefanos Leptidis, Guiseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsenen, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, Emil Hansson, Taija Mäkinen, Xiao-Rong Peng, Thomas D. Arnold, Kari Alitalo, Lars I Eriksson, Urban Lendahl, Christer Betsholtz
bioRxiv 2020.05.11.088500; doi: https://doi.org/10.1101/2020.05.11.088500

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