Angiogenesis

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Angiogenesis

Pathway Description:

Angiogenesis is the formation of new blood vessels and can be induced by tumor growth, tissue wound, and inflammation. Rapid tumor cell growth creates intracellular hypoxia. 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 numerous target gene products. Secreted growth factors (such as VEGF, FGF, and TGF) induce signaling pathways (including PLCγ, PI3K, Src, and Smad signaling) that result in endothelial cell proliferation, increased vascular permeability, and cell migration. In addition to hypoxia, the PI3K and Ras pathways can increase HIF expression by promoting HIF translation.

Pericytes are support cells that provide structural support for newly formed blood vessels, promote endothelial cell survival, guide sprouting vessels, and regulate vasoconstriction and dilation. This is done through a reciprocal signaling mechanism in which PDGF-BB secreted into the matrix by endothelial cells acts as a ligand for PDGF receptor-β located on the pericyte membrane. In return, pericytes produce and secrete VEGF that signals through the endothelial VEGF receptor.

Extracellular matrix proteases and regulators induce tissue matrix remodeling in preparation for migration of endothelial cells from existing vessels to form new tubing. Tissue wounding, ischemia, or inflammation recruit macrophages and bone marrowderived inflammatory cells (BDMC) to wound areas and secrete a similar panel of proteins to induce angiogenesis.

Selected Reviews:

• Tie J, Desai J (2012) Antiangiogenic therapies targeting the vascular endothelia growth factor signaling system. Crit Rev Oncog 17(1), 51–67.
• Senger DR, Davis GE (2011) Angiogenesis. Cold Spring Harb Perspect Biol 3(8), a005090.
• Sakurai T, Kudo M (2011) Signaling pathways governing tumor angiogenesis. Oncology 81 Suppl 1, 24–9.
• Keith B, Johnson RS, Simon MC (2012) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12(1), 9–22.
• van Hinsbergh VW, Koolwijk P (2008) Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc. Res. 78(2), 203–12.
• Raza A, Franklin MJ, Dudek AZ (2010) Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am. J. Hematol. 85(8), 593–8.