The multitasking neutrophils and their involvement in angiogenesis

This review describes the mechanisms by which neutrophils contribute to angiogenesis in hypoxic tissues during different conditions and diseases (e.g., menstrual cycle, wound healing, ischemic diseases, cancers), with particular focus on the recently described proangiogenic neutrophil subpopulation.

The importance of neutrophils in initiation of angiogenesis has been described during the past decade, and is believed to occur through release of the well-known proangiogenic factors Bv8, vascular endothelial growth factor A, and matrix metalloproteinase 9. However, additional proangiogenic actions of neutrophils have been outlined this year, mediated through for example pyruvate kinase M2, 14,15-epoxyeicosatrienoic acid, and formation of neutrophil extracellular traps, although their distinct mechanisms of action remain partly unknown. Neutrophils can also limit angiogenesis by secreting for example neutrophil elastase and α-defensins, which generate angiostatic molecules and proteolytically inactivate proangiogenic factors, respectively. These opposing neutrophil actions can be the consequence of on-site education or recruitment of distinct subpopulations from circulation. Indeed, a circulating proangiogenic neutrophil subpopulation was recently described in mice and men, which was rapidly recruited to hypoxic tissues by vascular endothelial growth factor A.

These recent findings have highlighted the diversity of actions performed by neutrophils in the angiogenic process and identified new opportunities to regulate angiogenesis.