Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease

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.

VEGF receptor promotes hypoxia-induced hematopoietic progenitor proliferation and differentiation

Intermittent or chronic hypoxia is associated with morbidity and mortality in many diseases such as obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD), respectively. We found exaggerated inflammation with heightened numbers of inflammatory leukocytes in these patients compared with age-matched controls. Chronically hypoxic mice exhibited similar trend and induced proliferation of hematopoietic stem and progenitor cells (HSPC), precursors of inflammatory leukocytes. Consistently, a transcriptomic analysis of human HSPC exposed to hypoxic conditions revealed elevated expression of genes involved in progenitor mobilization. Additionally, bone marrow cells in mice under hypoxic conditions expressed high amount of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFr) and its target genes in hypoxic conditions. In silico and ChIP experiments demonstrated that HIF-1⍺ binds to the promoter region of VEGFr. These results indicate that VEGF signaling in HSPC is an important mediator of their proliferation and differentiation in hypoxia-induced inflammation and represents a potential therapeutic target to prevent aberrant inflammation in hypoxia-associated diseases.

Initiation of acute graft-versus-host disease by angiogenesis

Key Points Angiogenesis preceded infiltration of inflammatory leukocytes during GVHD as well as during experimental colitis. Metabolic alterations and cytoskeleton changes occurred during early angiogenesis, but classical endothelial activation signs were absent.

D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion

Lymphatic endothelial cells are important for efficient flow of antigen-bearing fluid and antigen-presenting cells (APCs) from peripheral sites to lymph nodes (LNs). APC movement to LNs is dependent on the constitutive chemokine receptor CCR7, although how conflicting inflammatory and constitutive chemokine cues are integrated at lymphatic surfaces during this process is not understood. Here we reveal a previously unrecognized aspect of the regulation of this process. The D6 chemokine-scavenging receptor, which is expressed on lymphatic endothelial cells (LECs), maintains lymphatic surfaces free of inflammatory CC-chemokines and minimizes interaction of inflammatory leukocytes with these surfaces. D6 does not alter the level of CCR7 ligands on LECs, thus ensuring selective presentation of homeostatic chemokines for interaction with CCR7+ APCs. Accordingly, in D6-deficient mice, inflammatory CC-chemokine adherence to LECs results in inappropriate perilymphatic accumulation of inflammatory leukocytes at peripheral inflamed sites and draining LNs. This results in lymphatic congestion and impaired movement of APCs, and fluid, from inflamed sites to LNs. We propose that D6, by suppressing inflammatory chemokine binding to lymphatic surfaces, and thereby preventing inappropriate inflammatory leukocyte adherence, is a key regulator of lymphatic function and a novel, and indispensable, contributor to the integration of innate and adaptive immune responses.