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.
Highlights
Myeloid cells, innate immune guardians against infection, become protagonists of cardiovascular disease (CVD) in the presence of hyperlipidemia[1,2,3]
To determine which hematopoietic stem and progenitor cells (HSPCs) are affected, we examined HSPCs in patients with arterial hypertension only, both hypertension and atherosclerosis or acute myocardial infarction (MI)
Our study addresses how the heart disease milestones hypertension, atherosclerosis and MI affect the bone marrow’s vascular health
Summary
Innate immune guardians against infection, become protagonists of cardiovascular disease (CVD) in the presence of hyperlipidemia[1,2,3]. The bone marrow vasculature encounters the same stimuli that instigate CVD elsewhere Countless such factors emerged from vascular biology research focusing on the heart and brain, for instance, (1) aberrant mechanical forces, for example, increased blood pressure altering vascular diameter, cell activation states, matrix deposition and vasomotor tone, (2) pathological metabolite blood content, for example, hyperlipidemia resulting in lipid deposits in the arterial wall, (3) reduced blood oxygen levels leading to angiogenesis or hypoxic cell death, (4) increased levels of circulating hormones, for example, angiotensin II (Ang-II), causing vasoconstriction, and (5) higher blood cytokine levels, for example, interleukins changing endothelial phenotypes. Our data add a missing link to the vicious inflammatory cycle that propels CVDs by identifying bone marrow vascular pathologies that augment the supply of leukocytes implicated in these conditions
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