Bone Marrow Vascular Pathologies Augment Supply of Leukocytes Implicated in CVD

It's well documented that leukocytes contribute to the vicious inflammatory cycle that promotes the progression of cardiovascular disease (CVD). But there's a gap in knowledge: what causes the bone marrow to increase leukocyte output?

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Researchers at Massachusetts General Hospital have discovered CVD affects bone marrow endothelial cells, which are key hematopoietic cells, and their interactions with hematopoietic progenitors. In addition, major vascular alterations in bone marrow gave rise to systemic leukocytosis and the overproduction of other inflammatory myeloid cells—and the researchers are already experimenting with therapies to prevent those changes.

David Rohde, MD, instructor in investigation at the Center for Systems Biology in the Mass General Research Institute, Katrien Vandoorne, PhD, also of the center, Matthias Nahrendorf, MD, PhD, Weissman Family MGH Research Scholar 2014-2019, the Richard Moerschner Endowed MGH Research Institute Chair, and investigator in the center, and colleagues report their findings in Nature Cardiovascular Research.

Human Bone Marrow and CVD

The research team began by examining bone marrow samples from patients with hypertension only, both hypertension and atherosclerosis, or recent acute myocardial infarction (MI). All three conditions affected the entire hematopoietic hierarchy, from hematopoietic stem cells to myeloid progenitors.

The team studied the three conditions separately in mice to examine how each one influences progenitor cells.

Vascular Anatomy Altered in Bone Marrow

The researchers observed that CVD profoundly affected the structure of the bone marrow vasculature:

• Mice with hypertension or atherosclerosis showed increased arteriolar wall thickness, which influences molecular interactions of endothelial cells with hematopoietic stem and progenitor cells (HSPCs)
• Mice with hypertension and especially those with acute MI had increased growth of new blood vessels, and in the post-MI mice this angiogenesis occurred in synchrony with the emergency hematopoiesis and leukocytosis induced during MI

Vascular Function Altered in Bone Marrow

Imaging suggested the anatomical adaptations of the bone marrow vasculature to CVD lead to altered vascular function:

• Mice with hypertension or MI had evidence of integrin activation during angiogenesis
• In all three conditions, vascular leakage accelerated, which facilitates trafficking of cells and blood-borne signals across the bone marrow endothelium, potentially spurring HSPC activation and increasing leukocytosis
• Endothelial dysfunction (impaired vasodilation response), a hallmark of CVD, was noted in all three conditions

Laying the Groundwork for Novel Interventions

The researchers also report intriguing results from gene knockout studies: limiting angiogenesis with endothelial deletion of Vegfr2 reduced emergency hematopoiesis after MI, and endothelial deletion of Il6 (which encodes interleukin-6) or Vcan (which encodes versican) reduced hematopoiesis and the number of myeloid cells in mice with atherosclerosis or MI.

Further study of the bone marrow vasculature in CVD is expected to lead to new approaches for preventing and treating cardiovascular inflammation and disease.

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