Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease

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 lead to 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 Vegf receptor 2 curbed emergency hematopoiesis after myocardial infarction. We noted that bone marrow endothelial cells assumed inflammatory transcriptional phenotypes in all examined stages of cardiovascular disease. Endothelial deletion of Interleukin 6 or Versican, genes shown to be highly expressed in mice with atherosclerosis or myocardial infarction, reduced hematopoiesis and systemic myeloid cell numbers in those conditions. Our findings establish that cardiovascular disease remodels the vascular bone marrow niche, stimulating hematopoiesis and production of inflammatory leukocytes.