Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors

Angiogenesis is the development of blood vessels from an existing vasculature. This process is fundamental to both physiological wound healing and the growth of malignant tumors, as it restores or creates a blood supply to growing tissue. In both cases, the release of angiogenic molecules by macrophages recruited to the wound or tumor site is central to the formation of these neovessels. Reduced vascular perfusion in tissues generates tissue ischemia and a marked reduction in local levels of oxygen (hypoxia) and glucose. Cells adapt by switching to anaerobic metabolic pathways, with a concomitant increase in lactate production and reduction in extracellular pH. In tumors, these microenvironmental "stress" factors stimulate tumor cells to secrete a wide array of proangiogenic cytokines and enzymes, promoting the re-establishment of a local vascular supply. Here we review the evidence that these stress factors, in particular hypoxia and high lactate levels, stimulate macrophages to perform similar proangiogenic functions in both tumors and wounds. The resolution of wounds results in restoration of tissue integrity and perfusion, and macrophage presence is reduced to preinjury levels. However, in tumors a high number of macrophages persists and might contribute to the ongoing growth, neovascularization, and metastasis of malignant cells.