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Microvasculature dysfunction is associated with COPD\/emphysema. However, it is not known if abnormal endothelium drives COPD\/emphysema pathology and\/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD\/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich \u03b1-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and\/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD\/emphysema.<\/jats:p>","DOI":"10.1084\/jem.20200938","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T02:21:56Z","timestamp":1621304516000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["Reversal of emphysema by restoration of pulmonary endothelial cells"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2830-755X","authenticated-orcid":true,"given":"Shu","family":"Hisata","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY 1"},{"name":"Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan 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