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.