Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease

David Rohde, Katrien Vandoorne, I-Hsiu Lee, Jana Grune, Shuang Zhang, Cameron S McAlpine, Maximilian J Schloss, Ribhu Nayar, Gabriel Courties, Vanessa Frodermann, Gregory Wojtkiewicz, Lisa Honold, Qi Chen, Stephen Schmidt, Yoshiko Iwamoto, Yuan Sun, Sebastian Cremer, Friedrich F Hoyer, Oriol Iborra-Egea, Christian Muñoz-GuijosaFei Ji, Bin Zhou, Ralf H Adams, Joshua D Wythe, Juan Hidalgo, Hideto Watanabe, Yookyung Jung, Anja M van der Laan, Jan J Piek, Youmna Kfoury, Pauline A Désogère, Claudio Vinegoni, Partha Dutta, Ruslan I Sadreyev, Peter Caravan, Antoni Bayes-Genis, Peter Libby, David T Scadden, Charles P Lin, Kamila Naxerova, Filip K Swirski, Matthias Nahrendorf

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Abnormal hematopoiesis advances cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and the heart. The bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, but whether cardiovascular disease affects the hematopoietic organ's microvasculature is unknown. Here we show that hypertension, atherosclerosis and myocardial infarction (MI) instigate endothelial dysfunction, leakage, vascular fibrosis and angiogenesis in the bone marrow, altogether leading to overproduction of inflammatory myeloid cells and systemic leukocytosis. Limiting angiogenesis with endothelial deletion of Vegfr2 (encoding vascular endothelial growth factor (VEGF) receptor 2) curbed emergency hematopoiesis after MI. We noted that bone marrow endothelial cells assumed inflammatory transcriptional phenotypes in all examined stages of cardiovascular disease. Endothelial deletion of Il6 or Vcan (encoding versican), genes shown to be highly expressed in mice with atherosclerosis or MI, reduced hematopoiesis and systemic myeloid cell numbers in these conditions. Our findings establish that cardiovascular disease remodels the vascular bone marrow niche, stimulating hematopoiesis and production of inflammatory leukocytes.

Original languageEnglish
Pages (from-to)28-44
Number of pages17
JournalNature cardiovascular research
Volume1
Issue number1
DOIs
Publication statusPublished - Jan 2022

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