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

Liqun He, Maarja Andaloussi Mäe, Lars Muhl, Ying Sun, Riikka Pietilä, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Lei Zhang, Yuan Xie, Stefanos Leptidis, Giuseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsänen, Olivier Mirabeau, Emil Hansson, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, 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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Lars Muhl
2Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
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Ying Sun
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Riikka Pietilä
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 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 Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
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Guillem Genové
2Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, 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 Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
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Giuseppe Mocci
2Integrated Cardio Metabolic Centre (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 Räsänen
6Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland
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Olivier Mirabeau
7Chemin des demoiselles Melson 2, 92160 Antony, France
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Emil Hansson
2Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
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Johan Björkegren
2Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
8Institute of Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, US
9Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
10Clinical Gene Networks AB, Stockholm, Sweden
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Michael Vanlandewijck
2Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
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Klas Blomgren
5Department of Women’s and Children’s Health, Karolinska Institutet, Solna, Sweden
11Department of Pediatric oncology, Karolinska University Hospital, Stockholm, Sweden
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Taija Mäkinen
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Xiao-Rong Peng
12Cardiovascular, Renal and Metabolism (CVRM), IMED Biotech Unit, AstraZeneca BioPharmaceuticals R&D, Gothenburg, Sweden
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Thomas D. Arnold
13Department 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 Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
14Department 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 Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
15Department 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 implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors.

Competing Interest Statement

C.B. is a consultant for AstraZeneca BioPharmaceuticals R&D. X.-R. P. is an employee of AstraZeneca BioPharmaceuticals R&D.

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Posted July 26, 2020.
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Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19
Liqun He, Maarja Andaloussi Mäe, Lars Muhl, Ying Sun, Riikka Pietilä, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Lei Zhang, Yuan Xie, Stefanos Leptidis, Giuseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsänen, Olivier Mirabeau, Emil Hansson, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, 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
Liqun He, Maarja Andaloussi Mäe, Lars Muhl, Ying Sun, Riikka Pietilä, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Lei Zhang, Yuan Xie, Stefanos Leptidis, Giuseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsänen, Olivier Mirabeau, Emil Hansson, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, 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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