Angiogenesis is the formation of new blood vessels from the pre-existing blood vessels. Blood vessels are composed of endothelial cells and supporting musculature. Angiogenesis is regulated by numerous soluble ligands and by cell-matrix interactions. We have studied the molecular mechanisms in fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-A (VEGF-A)-induced angiogenesis using immortalized endothelial cell lines in different angiogenesis assays.The role of the signaling protein H-Ras in FGF-2-induced in vitro angiogenesis was studied by expressing mutated versions of H-Ras in immortalized mouse brain endothelial cells using a tetracycline-regulated expression system. In vitro angiogenesis was analyzed as the ability of cells to invade a fibrin matrix and form branching structures in response to a combination of FGF-2 and tumor necrosis factor-α (TNF-α). Inhibition of H-Ras through the expression of dominant negative (S17N) H-Ras or pharmacological inactivation of H-Ras with a farnesyl transferase inhibitor, did not inhibit growth factor-induced invasion. In contrast, expression of constitutively active (G12V) H-Ras caused cells to adopt a transformed phenotype which inhibited invasive growth and cells formed solid tumors when injected in nude mice. These studies suggest that H-Ras activity is not required for differentiation but its activity must be tightly regulated as aberrant activity impairs endothelial cell differentiation…
Contents
Introduction
Formation of blood vessels – Angiogenesis and vasculogenesis
Angiogenesis in health and disease
Signals regulating angiogenesis
Receptor tyrosine kinase signaling
FGF and FGF receptors
VEGF and VEGF receptors
VEGF-A and its actions
Intracellular signaling molecules regulated by FGF and VEGF
Ras
Src
Methods to study the regulation of angiogenesis
Model systems that mimic angiogenesis
Inducible gene expression systems for mammalian cells
Gene profiling – an approach to study changes in gene expression
Present investigations
Paper I
Paper I
Paper III & IV
Future perspectives
Acknowledgement
References
Author: Rennel, Emma
Source: Uppsala University Library
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