Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome

David R. Price, Elisa Benedetti, Katherine L. Hoffman, Luis Gomez-Escobar, Sergio Alvarez-Mulett, Allyson Capili, Hina Sarwath, Christopher N. Parkhurst, Elyse Lafond, Karissa Weidman, Arjun Ravishankar, Jin Gyu Cheong, Richa Batra, Mustafa Büyüközkan, Kelsey Chetnik, Imaani Easthausen, Edward J. Schenck, Alexandra C. Racanelli, Hasina Outtz Reed, Jeffrey LaurenceSteven Z. Josefowicz, Lindsay Lief, Mary E. Choi, Frank Schmidt, Alain C. Borczuk, Augustine M.K. Choi, Jan Krumsiek, Shahin Rafii

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)–induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

Original languageEnglish (US)
Pages (from-to)1001-1015
Number of pages15
JournalAmerican Journal of Pathology
Volume192
Issue number7
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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