Angiogenesis results in the formation of new blood vessels. Tumor growth, tissue wound and inflammation can induce angiogenesis. Rapid tumor cell growth creates intracellular hypoxia, which initiates a series of cell signaling events that promote angiogenesis. Hypoxia-inducible factor (HIF) is a transcription factor that responds to changing intracellular oxygen concentration. Under typical oxygen levels (normoxia), HIF is hydroxylated and acetylated, modifications that target the transcription factor for VHL mediated ubiquitin degradation. During hypoxia, HIF accumulates and is transported to the nucleus where it induces expression of a wide variety of target gene products, including proteins important for inducing tumor endothelial cell angiogenesis. Growth factors (such as VEGF, FGF, and TGF) induce signaling pathways (including PLCγ, PI3K, Src, Smad signaling) that result in endothelial cell proliferation, increase vascular permeability and cell migration. Extracellular matrix proteases and regulators induce tissue matrix remodeling in preparation for migration of endothelial cells from existing vessels to form new tubing. Cytokines promote additional tumor growth and induce the expression of signaling proteins (i.e. Slit2) that promote the creation of tumor-associated blood vessels. In addition to hypoxia, PI3K and Ras pathways can increase HIF expression by promoting HIF translation. Tissue wounding, ischemia or inflammation recruit macrophage and bone marrow-derived inflammatory cells (BDMC) to wound areas, where these monocytes induce a similar panel of secreted proteins to induce angiogenesis.
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