@article{bfe17e3d055e430ab4b9fe7078cc35d5,
title = "Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19",
abstract = "Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.",
author = "{MGH COVID-19 Collection and Processing Team,3,5,11} and Schmaier, {Alec A.} and {Pajares Hurtado}, {Gabriel M.} and Manickas-Hill, {Zachary J.} and Sack, {Kelsey D.} and Chen, {Siyu M.} and Victoria Bhambhani and Juweria Quadir and Nath, {Anjali K.} and Collier, {Ai Ris Y.} and Debby Ngo and Barouch, {Dan H.} and Shapiro, {Nathan I.} and Gerszten, {Robert E.} and Yu, {Xu G.} and Peters, {Kevin G.} and Robert Flaumenhaft and Parikh, {Samir M.}",
note = "Funding Information: The authors would like to thank Jonathan Hecht for directing the COVID-19 autopsy program, including the acquisition and processing tissue specimens, assembly of pathology reports, and obtaining appropriate control specimens. We greatly appreciate Michelle Hacker, Jonathan Li, and Michael Seaman{\textquoteright}s support with the COVID-19 biorepositories. We thank Christiane Ferran, Cleide Angolano, and Johannes Schlondorff for their assistance in establishing the BSL2+ facility for sample processing. We are grateful to Shulin Lu for assistance with Luminex assays. We appreciate Lay-Hong Ang, Anikit Gad and the BIDMC Histology and Confocal Imaging Core for assistance with immunofluorescence staining. We would like to thank Karla Pollick and Stephanie Li from the BIDMC InSIGHT Core for help with clinical data collection. The authors acknowledge the following groups and individuals: the CORE Steering Committee members Laurie Farrell, Aarti Asnani, Elias Baedorf-Kassis, Valerie Banner-Goodspeed, Somnath Bose, Daniel Katz, Douglas Krakower, Michelle Lai, Anica Law, Jaymin Patel, Nathan Shapiro, Gyongyi Szabo, and Jeffery Zwicker as well as the numerous research assistants and fellows who contributed to data collection. The authors thank the participants and their families, the frontline healthcare providers, and the laboratory staff of the BIDMC COVID-19 Biorepository and MGH/MassCPR COVID-19 Biorepository (see Supplemental Acknowledgments). See Supplemental Acknowledgments for MGH COVID-19 Collection and Processing Team details. We also are grateful to the Center for Virology and Vaccine Research, the Harvard Catalyst Clinical Research Center, the BIDMC Department of Obstetrics and Gynecology, the Cardiovascular Institute at BIDMC, and the office of the BIDMC Chief Academic Officer for enrollment, collection, and processing samples for the BIDMC COVID-19 Biorepository. This work was supported by a Massachusetts Consortium on Pathogen Readiness (MassCPR) Evergrande COVID-19 Response Fund award (to AAS, RF, and SMP), a North American Thrombosis Forum COVID-19 Research Initiative award (to AAS), the John S. LaDue Memorial Fellowship (to AAS), and the NIH (R35HL139424 to SMP, R35HL007917 to RF, and R01HL14922 to NIS). Funding Information: The authors would like to thank Jonathan Hecht for directing the COVID-19 autopsy program, including the acquisition and processing tissue specimens, assembly of pathology reports, and obtaining appropriate control specimens. We greatly appreciate Michelle Hacker, Jonathan Li, and Michael Seaman{\textquoteright}s support with the COVID-19 biorepositories. We thank Christiane Ferran, Cleide Angolano, and Johannes Schlon-dorff for their assistance in establishing the BSL2+ facility for sample processing. We are grateful to Shulin Lu for assistance with Luminex assays. We appreciate Lay-Hong Ang, Anikit Gad and the BIDMC Histology and Confocal Imaging Core for assistance with immunofluorescence staining. We would like to thank Karla Pollick and Stephanie Li from the BIDMC InSIGHT Core for help with clinical data collection. The authors acknowledge the following groups and individuals: the CORE Steering Committee members Lau-rie Farrell, Aarti Asnani, Elias Baedorf-Kassis, Valerie Banner-Goodspeed, Somnath Bose, Daniel Katz, Douglas Krakower, Michelle Lai, Anica Law, Jaymin Patel, Nathan Shapiro, Gyongyi Szabo, and Jeffery Zwicker as well as the numerous research assistants and fellows who contributed to data collection. The authors thank the participants and their families, the frontline healthcare providers, and the laboratory staff of the BIDMC COVID-19 Biorepository and MGH/MassCPR COVID-19 Biorepository (see Supplemental Acknowledgments). See Supplemental Acknowledgments for MGH COVID-19 Collection and Processing Team details. We also are grateful to the Center for Virology and Vaccine Research, the Harvard Catalyst Clinical Research Center, the BIDMC Department of Obstetrics and Gynecology, the Cardiovascular Institute at BIDMC, and the office of the BIDMC Chief Academic Officer for enrollment, collection, and processing samples for the BIDMC COVID-19 Biorepository. This work was supported by a Massachusetts Consortium on Pathogen Readiness (MassCPR) Evergrande COVID-19 Response Fund award (to AAS, RF, and SMP), a North American Thrombosis Forum COVID-19 Research Initiative award (to AAS), the John S. LaDue Memorial Fellowship (to AAS), and the NIH (R35HL139424 to SMP, R35HL007917 to RF, and R01HL14922 to NIS). Publisher Copyright: {\textcopyright} 2021, Schmaier et al.",
year = "2021",
month = oct,
day = "22",
doi = "10.1172/jci.insight.151527",
language = "English (US)",
volume = "6",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "20",
}