Selected Reviews

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.

VEGF Pathway

Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells
Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta
Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization
Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium
Activation of endothelial cell mitogen activated protein kinase ERK(1/2) by extracellular HIV-1 Tat protein
Regulation of the acute myeloid leukemia cell line OCI/AML-2 by endothelial nitric oxide synthase under the control of a vascular endothelial growth factor signaling system
VEGF receptor signal transduction
Sphingosine 1-phosphate induces membrane ruffling and increases motility of human umbilical vein endothelial cells via vascular endothelial growth factor receptor and CrkII
Prognostic significance of vascular endothelial growth factor D in gastric carcinoma
Vascular endothelial growth factor in the lung