Macrophages exist in distinct differentiation states. Proangiogenic/immunosuppressive (M2-like) macrophages and antitumoral/proinflammatory (M1-like) macrophages represent two extremities of a continuum. Because lineage-defined subsets have not been identified yet, macrophage heterogeneity is likely to reflect the plasticity of these cells in response to microenvironmental signals. The concept that hypoxia can induce inflammation has gained general acceptance. However, little is known on how extravasated monocytes and their macrophage progeny react to a condition of low oxygen. Different macrophage phenotypes have been positively and negatively associated with the clinical outcome of vascular disorders as cancer and ischemia. These pathological conditions are characterized not only by dysfunctional vessels, which impair oxygenation, but also by strong immunoregulatory responses. Recently we have shown that reduced activity of the oxygen sensor PHD2 in macrophages skews their polarization towards a proarteriogenic (M2-like) phenotype, which confers protection against ischemia. Based on these findings, we propose to dissect upstream and downstream signals to the oxygen sensing machinery and hypoxia-response in macrophages. By using a genome-wide transcriptional profiling approach and a high-throughput interactome analysis, combined with mouse genetic tools, we will identify the gene signature of macrophages in hypoxia and unravel the molecular executors of this response. The identification of the effectors responsible for macrophage skewing in relation to oxygen availability will contribute to a better understanding of immunoregulatory cues during disease progression and unveil the multifaceted function of macrophages during vessel formation. With the focus of our research on macrophage manipulation towards a desired phenotype, we will offer new treatment options for cancer and ischemia that might result in optimized therapies and overcome resistance to current drugs.
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