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Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19
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.
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“Multiple immunostaining studies reveal that ACE2 protein in the human brain is predominantly or exclusively expressed in vasculature (and specifically expressed within pericytes) (52, 53, 70), and many neurological symptoms associated with CoV-2 infection like stroke or altered consciousness are consistent with an underlying vasculopathy (71-76).”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [70]
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“In addition, our findings support recent reports of pericyte-specific vascular expression of ACE2 in brain and heart tissue (Chen et al., 2020; He et al., 2020).”
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Roberts, K. A., Colley, L. S., Agbaedeng, T. A., Ellison, G. M., & Ross, M. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.598400 · Cited by 96
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“ACE2 is the proposed receptor for SARS-CoV-2, and in the alveolus, it is expressed predominantly (if not solely) by AT2.(57) Critical to gas exchange and pulmonary function, the alveolar capillary unit is the primary site of injury in COVID-19.”
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“Interestingly, a recent study demonstrated that ACE2 in the brain is not expressed in the vascular endothelial cells but instead in pericytes.(89) Several single‐cell RNA‐seq studies have identified a high level of ACE2 in pericytes.”
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“This finding is in accordance with various published studies, which showed that ABCC9 is highly expressed in pericytes and could be a biomarker for it [17,65,66].”
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Endothelial Cell Metabolism in Vascular Functions
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“Interestingly, recent studies have highlighted the role of pericytes in the onset of vasculopathies and pro-thrombotic conditions in coronavirus disease 2019 (COVID-19)-positive patients [19], endorsing the role of these perivascular cells as a potential therapeutic target in vascular diseases and neurological disorde…”
BackgroundCentral Nervous System Pericytes Contribute to Health and Disease
Girolamo, F., Errede, M., Bizzoca, A., Virgintino, D., & Ribatti, D. (2022) · Cells · doi:10.3390/cells11101707 · Cited by 32
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Dysautonomia and Implications for Anosmia in Long COVID-19 Disease
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“Thus, the SARS-CoV-2 virus can either travel via peripheral blood vessels causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction, or reach the systemic circulation and take a different route to the blood–brain barrier, damaging the blood–brain barrier leading to neuroinflammatio…”
BackgroundNeurochemical biomarkers to study CNS effects of COVID‐19: A narrative review and synthesis
Edén, A., Simrén, J., Price, R. W., Zetterberg, H., & Gisslén, M. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15459 · Cited by 29
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BackgroundBiomaterial-based immunoengineering to fight COVID-19 and infectious diseases
Zarubova, J., Zhang, X., Hoffman, T., Hasani‐Sadrabadi, M. M., & Li, S. (2021) · Matter · doi:10.1016/j.matt.2021.02.025 · Cited by 28
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“Those data were consistent with previous reports that pericytes instead of endothelial cells expressed ACE2 [50, 51].”
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Endothelial Dysfunction in SARS-CoV-2 Infection
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“Although there was an unusual endothelial ACE2 expression, contamination from adherent pericyte fragments made it possible to determine a common confounder in vascular single-cell RNA sequencing data [97].”
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Wazny, V. K., Siau, A., Wu, K. X., & Cheung, C. (2020) · Open Biology · doi:10.1098/rsob.200208 · Cited by 24
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“A study posted in bioRxiv stated that ACE2 was specifically expressed in microvascular pericytes, but absent in the endothelial cells and perivascular macrophages.(58) It is intriguing to pinpoint pericytes as the main ACE2-expressing cells in the vasculature.”
BackgroundIsolation of Murine Primary Aortic Smooth Muscle Cells
Hubert, M. O., Rodríguez‐Vita, J., Wiedmann, L., & Fischer, A. (2021) · BIO-PROTOCOL · doi:10.21769/bioprotoc.3907 · Cited by 23
“…Cells of the blood vessel wall (mural cells) are critically involved in the regulation of several disorders, from hypertension (Rodríguez-Vita et al., 2005a) and atherosclerosis (Rodríguez-Vita et al., 2008) to cancer (Wong et al., 2020) and more recently even COVID-19 (He et al., 2020).”
BackgroundPulmonary stromal expansion and intra-alveolar coagulation are primary causes of COVID-19 death
Székely, L., Bozóky, B., Béndek, M., Ostad, M., Lavignasse, P., Haag, L., Wu, J., Xu, J., Gupta, S., Saccon, E., et al. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e07134 · Cited by 23
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Recent insights into viral infections as a trigger and accelerator in alzheimer's disease
Vlieger, L. D., Vandenbroucke, R. E., & Hoecke, L. V. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.103340 · Cited by 16
Sequelae and Comorbidities of COVID-19 Manifestations on the Cardiac and the Vascular Systems
Batta, Y., King, C., Johnson, J. B., Haddad, N., Boueri, M. G., & Haddad, G. E. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.748972 · Cited by 14
Hirunpattarasilp, C., James, G., de Freitas, F. S. S., Sethi, H., Kittler, J. T., Huo, J., Owens, R. J., & Attwell, D. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.01.438122 · Cited by 15
Emerging neurotropic features of SARS-CoV-2
Zhan, W.-R., Huang, J., Zeng, P.-M., Tian, W.-Y., & Luo, Z. (2021) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjab044 · Cited by 14
“…expression of ACE2 was observed in human neurons in a subtype- and region-specific manner, and high expression of ACE2 and TMPRSS2 was observed in pericytes, endothelial cells, or choroid plexus cells (He et al., 2020; Jacob et al., 2020; Ramani et al., 2020; Chen et al., 2021; Song et al., 2021).”
BackgroundSpike protein multiorgan tropism suppressed by antibodies targeting SARS-CoV-2
Brady, M., McQuaid, C., Solorzano, A. G., Johnson, A., Combs, A. L., Venkatraman, C., Rahman, A., Leyva, H., Kwok, W. E., Wood, R. W., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02856-x · Cited by 12
McQuaid, C., Solorzano, A. G., Dickerson, I. M., & Deane, R. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1117845 · Cited by 12
“, 2020), and in pericytes and vascular smooth muscle cells (He et al., 2020).”
BackgroundCoate, K. C., Cha, J., Shrestha, S., Wang, W., Gonçalves, L. M., Almaça, J., Kapp, M. E., Fasolino, M., Morgan, A., Dai, C., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.31.275719 · Cited by 12
Unraveling the SARS-CoV-2 spike protein long-term effect on neuro-PASC
Menezes, F., Palmeira, J. D. F., Oliveira, J. D. S., Argañaraz, G. A., Soares, C. R. J., Nóbrega, O. D. T., Ribeiro, B. M., & Argañaraz, E. R. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1481963 · Cited by 10
Mechanism of COVID-19-Induced Cardiac Damage from Patient, In Vitro and Animal Studies
Jones, E. A. V. (2023) · Current Heart Failure Reports · doi:10.1007/s11897-023-00618-w · Cited by 11
COVID-19: The Impact on Cardiovascular System
Šikić, J., Planinić, Z., Matišić, V., Friščić, T., Molnar, V., Jagačić, D., Vujičić, L., Tudorić, N., Gršić, L. P., Ljubičić, Đ., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9111691 · Cited by 10
“Furthermore, it has been demonstrated that pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 is playing a critical role in microvascular inflammation and hypercoagulopathy in COVID-19 patients [24].”
BackgroundBurel‐Vandenbos, F., Cardot‐Leccia, N., & Passeron, T. (2020) · Intensive Care Medicine · doi:10.1007/s00134-020-06220-1 · Cited by 10
“Expression of ACE2 in lung pericytes is not increased in mice but remains unknown in humans [6].”
BackgroundCrosstalk between SARS-CoV-2 Infection and Neurological Disorders: A Review
Azhar, A., Wali, M. A., Rashid, Q., Khan, W. H., Alhosaini, K. A., Owais, M., & Kamal, M. A. (2022) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527321666220418114009 · Cited by 8
Daems, M., Liesenborghs, L., Boudewijns, R., Simmonds, S. J., Kraisin, S., Van Wauwe, J., Cuijpers, I., Raman, J., Geuens, N., Buyten, T. V., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.964512 · Cited by 8
“In heart (27, 28) and brain tissue (28, 29), pericytes express ACE2, rendering them a likely target of cardiac SARS-CoV-2 infection.”
BackgroundCadamuro, M., Lasagni, A., Radu, C. M., Calistri, A., Pilan, M., Valle, C., Bonaffini, P. A., Vitiello, A., Toffanin, S., Venturin, C., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.06.014 · Cited by 11
Apoptosis and pericyte loss in alveolar capillaries in COVID-19 infection: choice of markers matters
Jain, A., & Doyle, D. J. (2020) · Intensive Care Medicine · doi:10.1007/s00134-020-06208-x · Cited by 8
“Third, though pericytes have been identified as the cells with high expression of ACE2 in organs such as heart and brain, lung pericytes seem to be deficient in ACE2 [4].”
BackgroundInfluentialGao, S., Tang, A. T., Wang, M., Buchholz, D. W., Imbiakha, B., Yang, J., Chen, X., Hewins, P., Mericko-Ishizuka, P., Leu, N. A., et al. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1266276 · Cited by 7
Vascular inflammation in the central nervous system
Guo, X., & Zhao, Z. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.332140 · Cited by 7
Severe Acute Respiratory Syndrome Coronavirus 2 Vasculopathy in a Syrian Golden Hamster Model
Ball, E. E., Weiss, C. M., Liu, H., Jackson, K., Keel, M. K., Miller, C. J., Rompay, K. K. A. V., Coffey, L. L., & Pesavento, P. A. (2023) · American Journal Of Pathology · doi:10.1016/j.ajpath.2023.02.013 · Cited by 7
“The American Journal of Pathology - ajp.amjpathol.org endothelium and express the SARS-CoV-2 receptor angiotensin-converting enzyme 2.31e33 Overall, attempts to localize viral antigen/RNA to endothelial cells have been largely unsuccessful, equivocal,26,28,34e37 or only possible at early time points, where it associat…”
Sphingosine-1-Phosphate as Lung and Cardiac Vasculature Protecting Agent in SARS-CoV-2 Infection
Karam, M., & Auclair, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713088 · Cited by 7
Dondi, A., Sperti, G., Gori, D., Guaraldi, F., Montalti, M., Parini, L., Piraccini, B. M., Lanari, M., & Neri, I. (2022) · European Journal of Pediatrics · doi:10.1007/s00431-022-04585-7 · Cited by 9
“hypothesized some possible pathogenetic mechanisms [4]: (1) an early, strong interferon type I response against the viral infection that might attenuate viral replication, but induce microangiopathic changes producing a chilblain-like eruption (virus-induced type I interferonopathy hypothesis); (2) chilblains as a man…”
BackgroundXie, Y., Chen, S., Wang, X., Li, B., Zhang, T., He, X., Sun, N., Wang, L., Zeng, H., & Shen, Y. (2020) · medRxiv · doi:10.1101/2020.07.06.20147256 · Cited by 7
Self-citationArppo, A., Barker, H. R., & Parkkila, S. (2024) · PLoS ONE · doi:10.1371/journal.pone.0307731 · Cited by 6
Nickl, R., Hauser, S., Pietzsch, J., & Richter, T. (2023) · Bioengineering · doi:10.3390/bioengineering10010117 · Cited by 7
SARS-CoV-2 and Pre-existing Vascular Diseases: Guilt by Association?
Voulalas, G., Tsui, J. C. S., Candilio, L., & Baker, D. (2021) · Clinical Medicine Insights Cardiology · doi:10.1177/11795468211010705 · Cited by 6
Models for COVID-19 Early Cardiac Pathology Following SARS-CoV-2 Infection
Fremont‐Smith, M., Gherlone, N., Smith, N., Tisdall, P., & Ricke, D. O. (2021) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2021.09.052 · Cited by 7
Vashisht, A., Vashisht, V., Singh, H., Ahluwalia, P. K., Mondal, A. K., Williams, C., Farmaha, J. K., Woodall, J., & Kolhe, R. B. (2024) · Viruses · doi:10.3390/v16081183 · Cited by 5
Daems, M., Liesenborghs, L., Cuijpers, I., Boudewijns, R., Raman, J., Simmonds, S. J., Geuens, N., Lox, M., Verhamme, P. B., Linthout, S. V., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-105963/v1 · Cited by 5
Biasetti, L., Zervogiannis, N., Shaw, K., Trewhitt, H., Serpell, L. C., Bailey, D., Wright, E., & Hall, C. N. (2024) · Open Biology · doi:10.1098/rsob.230349 · Cited by 3
“ACE2 is expressed in pericytes, which are vascular mural cells that exist abluminally to endothelial cells, meaning pericytes can become infected with SARS-CoV-2 [22–24].”
BackgroundRenson, T., Hamiwka, L. A., & Benseler, S. M. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2022.931179 · Cited by 4
Khaddaj‐Mallat, R., Aldib, N., Paquette, A.-S., Ferreira, A., Lecordier, S., Bernard, M., Saghatelyan, A., & ElAli, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.30.442194 · Cited by 4
“It has been recently demonstrated that within the neurovascular interface, pericytes specifically express ACE2 [5], outlining their potential responsiveness to SARS-CoV-2 infection.”
BackgroundInfluentialMyocardial Angiotensin-Converting Enzyme 2 Protein Expression in Ischemic Heart Failure
Siratavičiūtė, V., Pangonytė, D., Utkienė, L., Jusienė, L., Marcinkevičienė, J. E., Stanionienė, Z., & Radikė, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417145 · Cited by 2
“He et al. noted that not all cardiac capillary pericytes were strongly ACE2 positive; some were weakly positive, and some were negative [49].”
BackgroundКОРОНАВИРУСНАЯ ИНФЕКЦИЯ И COVID-19 У ДЕТЕЙ. ЧАСТЬ 1. ЭПИДЕМИОЛОГИЯ, ЭТИОЛОГИЯ, ПАТОГЕНЕЗ
Косенкова, Т. В., Тимченко, В. Н., Леонидовна, Б. С., Маратовна, Ч. Т., Шакмаева, М. А., Булина, О. В., & Егорова, И. А. (2024) · Children s medicine of the North-West · doi:10.56871/cmn-w.2024.86.55.002 · Cited by 2
Зубко, А. В., Sabgayda, T. P., Ivanova, A., Николаевна, Е. Г., Zaporozhchenko, V. G., & Стародубов, В. И. (2021) · Annals of the Russian academy of medical sciences · doi:10.15690/vramn1496 · Cited by 2
Possibilities of sulodexide use in clinical practice
Morozov, A. M., Avanesyan, A. E., Boltik, A. A., & Sergeev, A. N. (2023) · Meditsinskiy sovet = Medical Council · doi:10.21518/ms2022-050 · Cited by 2
Костинов, М. П., Zhang, C., Khrapunova, I. A., Pechenik, A. S., Utkin, V. A., Локтионова, М. Н., Mashilov, K. V., & Soloveva, I. L. (2023) · Russian Journal of Immunology · doi:10.46235/1028-7221-13983-tdc · Cited by 2
Endocrinology, Diabetes and Obesity
(2018) · Endocrinology Diabetes and Obesity · doi:10.31532/endocrinoldiabetesobes · Cited by 2
McQuaid, C., Solorzano, A. G., Dickerson, I. M., & Deane, R. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.20.485050 · Cited by 2
“, 2020) , and in pericytes and vascular smooth muscle cells (He et al., 2020).”
Background
Metadata
- Authors
- He, L., Mäe, M. A., Muhl, L., Sun, Y., Pietilä, R., Nahar, K., Liébanas, E. V., Fagerlund, M. J., Oldner, A., Liu, J., Genové, G., Zhang, L., Xie, Y., Leptidis, S., Mocci, G., Stritt, S., Osman, A., Anisimov, A., Hemanthakumar, K. A., Räsänen, M., Mirabeau, O., Hansson, E., Björkegren, J., Vanlandewijck, M., Blomgren, K., Mäkinen, T., Peng, X.-R., Arnold, T. D., Alitalo, K., Eriksson, L. I., Lendahl, U., & Betsholtz, C.
- Affiliations
- Uppsala University (SE)
- Karolinska Institutet (SE)
- Karolinska University Hospital (SE)
- Shaanxi Normal University (CN)
- University of Helsinki (FI)
- University of California, San Francisco (US)
- Corresponding author
- Betsholtz, Christer
- ORCID
- He, Liqun
- Mäe, Maarja Andaloussi
- Muhl, Lars
- Sun, Ying
- Pietilä, Riikka
- Fagerlund, Malin Jonsson
- Oldner, Anders
- Liu, Jianping
- Genové, Guillem
- Zhang, Lei
- Xie, Yuan
- Leptidis, Stefanos
- Stritt, Simon
- Osman, Ahmed
- Anisimov, Andrey
- Hemanthakumar, Karthik Amudhala
- Mirabeau, Olivier
- Björkegren, Johan
- Vanlandewijck, Michael
- Blomgren, Klas
- Mäkinen, Taija
- Arnold, Thomas D.
- Alitalo, Kari
- Lendahl, Urban
- Betsholtz, Christer
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-05-12
- OpenAlex
- W3025656246
- Cited by
- 116
- References
- 99
- Citations by year
- 2024: 7 · 2023: 12 · 2022: 24 · 2021: 41 · 2020: 30
- Type
- posted content
- Language
- en
- Open access
- closed
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- AstraZeneca
- European Molecular Biology Organization (ALTF 86-2017)
- Familjen Erling-Perssons Stiftelse
- Indiana Corn Marketing Council
- European Commission
- Deutsche Forschungsgemeinschaft (STR 1538/1-1)
- Fondation Leducq
- Cancerfonden
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- SARS-CoV-2, ACE2, pericytes, microvascular inflammation, hypercoagulability, COVID-19 pandemic, endothelial cells, von Willebrand factor, platelet aggregation, organotypic co-culture, viral receptor expression
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