ArticleStem cell reports2022
A human pluripotent stem cell-based model of SARS-CoV-2 infection reveals an ACE2-independent inflammatory activation of vascular endothelial cells through TLR4.
Article in Stem cell reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- CD4Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- T1R3 Anchors ACE2 at the Pulmonary Endothelial Cell Surface to Attenuate Vascular Injury Following SARS-CoV-2 Spike 1 Protein Exposure In Vitro.Journal of cellular and molecular medicine · 2026Article
- SARS-CoV-2 enhances complement-mediated endothelial injury via the suppression of membrane complement regulatory proteins.Emerging microbes & infections · 2025Article
- CCL2-mediated endothelial injury drives cardiac dysfunction in long COVID.Nature cardiovascular research · 2024Article
- COVID-19 in the Initiation and Progression of Atherosclerosis: Pathophysiology During and Beyond the Acute Phase.JACC. Advances · 2024Review
- The emerging role of heart-on-a-chip systems in delineating mechanisms of SARS-CoV-2-induced cardiac dysfunction.Bioengineering & translational medicine · 2024Review
- SARS-CoV-2 infection activates inflammatory macrophages in vascular immune organoids.Scientific reports · 2024Article
- SARS-CoV-2 spike protein induces endothelial dysfunction in 3D engineered vascular networks.Journal of biomedical materials research. Part A · 2024Article
- SARS-CoV-2 infects epithelial cells of the blood-cerebrospinal fluid barrier rather than endothelial cells or pericytes of the blood-brain barrier.Fluids and barriers of the CNS · 2023Article
- Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19.Cell stem cell · 2023Article
- The role of the endothelium in severe acute respiratory syndrome coronavirus 2 infection and pathogenesis.Current opinion in physiology · 2023Review
- Vascular mechanisms of post-COVID-19 conditions: Rho-kinase is a novel target for therapy.European heart journal. Cardiovascular pharmacotherapy · 2023Article
- TLRs: Innate Immune Sentries against SARS-CoV-2 Infection.International journal of molecular sciences · 2023Review
- More than a key-the pathological roles of SARS-CoV-2 spike protein in COVID-19 related cardiac injury.Sports medicine and health science · 2023Review
- Integrative network pharmacology and in silico analyses identify the anti-omicron SARS-CoV-2 potential of eugenol.Heliyon · 2023Article
- Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome.The Journal of pharmacology and experimental therapeutics · 2023Article
- Article
- Review
- Locked in a pro-inflammatory state.eLife · 2022Article
- Activation of TLR4 by viral glycoproteins: A double-edged sword?Frontiers in microbiology · 2022Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To date, the direct causative mechanism of SARS-CoV-2-induced endotheliitis remains unclear. Here, we report that human ECs barely express surface ACE2, and ECs express less intracellular ACE2 than non-ECs of the lungs. We ectopically expressed ACE2 in hESC-ECs to model SARS-CoV-2 infection. ACE2-deficient ECs are resistant to the infection but are more activated than ACE2-expressing ones. The virus directly induces endothelial activation by increasing monocyte adhesion, NO production, and enhanced phosphorylation of p38 mitogen-associated protein kinase (MAPK), NF-κB, and eNOS in ACE2-expressing and -deficient ECs. ACE2-deficient ECs respond to SARS-CoV-2 through TLR4 as treatment with its antagonist inhibits p38 MAPK/NF-κB/ interleukin-1β (IL-1β) activation after viral exposure. Genome-wide, single-cell RNA-seq analyses further confirm activation of the TLR4/MAPK14/RELA/IL-1β axis in circulating ECs of mild and severe COVID-19 patients. Circulating ECs could serve as biomarkers for indicating patients with endotheliitis. Together, our findings support a direct role for SARS-CoV-2 in mediating endothelial inflammation in an ACE2-dependent or -independent manner.
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Registered trials
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