Summary Abnormal hematopoiesis promotes cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and heart. The bone marrow niche regulates the proliferation of hematopoietic stem cells and, therefore, the pool of systemic leukocytes, but it is unknown whether cardiovascular disease affects the microvasculature of the hematopoietic organ. Here we show that hypertension, atherosclerosis, and myocardial infarction (MI) cause endothelial dysfunction, leakage, vascular fibrosis, and angiogenesis in the bone marrow, 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) arrested emergency hematopoiesis after myocardial infarction. We observed 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 the number of systemic myeloid cells under these conditions. Our findings establish that cardiovascular disease remodels the vascular niche of the bone marrow, stimulating hematopoiesis and the production of inflammatory leukocytes. The traditional cardiovascular continuum connects known risk factors such as hypertension and hypercholesterolemia with diseases of the myocardium and larger arteries. The current data expand this concept to include important vascular alterations that influence the hematopoietic potential of the bone marrow. These observations provide new mechanistic insight into how crosstalk between common risk factors, the heart and vasculature link leukocytes to cardiovascular conditions. At a conceptual level, these feedback loops indicate that the study of bone marrow vasculature in CVD will identify new avenues to therapeutically target increased leukocytosis and systemic inflammation. |
Comments
Researchers report for the first time that cardiovascular disease affects blood vessels in the bone marrow and leads to increased production of white blood cells that cause inflammation, according to a study conducted in human bone marrow and in mice. The discovery could lead to new ways to prevent or treat heart disease, researchers say.
Researchers have known for some time that heart disease is associated with a buildup of white blood cells, which normally fight infections. Many of these cells are found in plaque, the accumulation of fats, cholesterol and other substances in the blood vessels, where they arrive after being born in the bone marrow and migrating through the bloodstream. But it’s unclear what leads to their increased bone marrow production, researchers say.
In the current study, the researchers showed that three different cardiovascular diseases (heart attack, atherosclerosis, and hypertension) affect the bone marrow in a way that increases white blood cell production. Each of these diseases can cause changes in the number of blood vessels in the bone marrow. They can also change the structure and function of bone marrow vessels and affect the release of factors that regulate white blood cell production and migration, the researchers found.
As a result, a greater buildup of white blood cells drives inflammation, including in the arteries and heart. That can restrict blood supply and potentially trigger a heart attack, researchers say.
"This study provides strong evidence that cardiovascular disease affects bone marrow vasculature and, consequently, blood stem cell activity ," said Michelle Olive, Ph.D., program officer for the Division of Sciences. NHLBI Cardiovascular. “This work sheds new light on the important role that the vascular bone marrow niche plays and how inflammation occurs. "It could lead to new targets and treatments for heart disease, the leading cause of death."
The study, funded in part by the NHLBI, appeared in Nature Cardiovascular ResearchExternal link.
