The regulation of angiogenesis by tissue cell-macrophage interactions
Michal Amit Rahat
Angiogenesis is the physiological process where new blood vessels grow from existing ones, in order to replenish tissues suffering from inadequate blood supply. Perhaps the most studied angiogenic process occurs in solid tumors whose growing mass and expanding cells create a constant demand for additional supply of oxygen and nutrients for survival. However, other physiological and clinical conditions, such as wound healing, ischemic events, autoimmune and age-related diseases also involve angiogenesis. Angiogenesis is a well-structured process that begins when oxygen and nutrients are depleted, leading to the release of chemokines and growth factors that attract immune cells, particularly macrophages and endothelial cells to the site. Macrophages that are recruited to the site, as well as tissue cells and endothelial cells, secrete pro-angiogenic mediators that affect endothelial cells and promote angiogenesis. These mediators include growth factors such as vascular endothelial cell growth factor (VEGF), matrix metalloproteinases (MMPs), as well as low levels of mediators that are usually seen as pro-inflammatory but are pro-angiogenic when secreted in low levels (e.g. nitric oxide (NO) and TNFa). Thus, macrophages play a major role in angiogenesis. Macrophages exhibit high plasticity and are capable of shifting between different activation modes and functions according to their changing microenvironment. Small differences in the composition of activating factors (e.g. TLR ligands such as LPS, anti-inflammatory cytokines, ECM molecules) in the microenvironment may differently activate macrophages to yield classically activated macrophages (or M1 macrophages) that can kill pathogen and tumor cells, alternatively activated macrophages (or M2 macrophages) that secrete antiinflammatory cytokines, resolution macrophages (rM?) that are involved in the resolution of inflammation, or regulatory macrophages (e.g. Myeloid-Derived Suppressor Cells - MDSCs) that control the function of other immune cells. In fact, macrophages may be activated in a spectrum of subsets that may differently contribute to angiogenesis, and in particular non-classically activated macrophages such as tumor-associated macrophages (TAMs) and Tie2-expressing monocytes (TEMs) can secrete high amounts of pro-angiogenic factors (e.g. VEGF, MMPs) or low levels of pro-inflammatory mediators (e.g. NO or TNFa) resulting in pro-angiogenic effects. Although the importance of macrophages as major contributors and regulators of the angiogenic process is well documented, less is known about the interactions between macrophages and other cell types (e.g. tumor cells, normal epithelial cells, endothelial cells) that regulate angiogenesis. We still have only limited understanding which proteins or complexes mediate these interactions and whether they require cell-cell contact (e.g. through integrins) or soluble factors (e.g. the EGF-CSF-1 loop), which signaling pathways are triggered in each of the two corresponding cell types, and how this leads to secretion of pro- or antiangiogenic factors in the microenvironment. The regulation of such interactions and through them of angiogenesis, whether through post-translational modifications of proteins or via the involvement of microRNA, is still unclear. The goal of this Research Topic is to highlight these interactions and their regulation in the context of both physiological and pathological conditions.