PDGF and Vessel Maturation
Pericytes are smooth muscle-like cells found in close contact with the endothelium in capillaries, where they regulate the morphology and function of the vessels. During vessel formation, platelet-derived growth factor-BB (PDGF-BB) is required for the rec
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Carina Hellberg, Arne Östman, and C.-H. Heldin
Abstract Pericytes are smooth muscle-like cells found in close contact with the endothelium in capillaries, where they regulate the morphology and function of the vessels. During vessel formation, platelet-derived growth factor-BB (PDGF-BB) is required for the recruitment and differentiation of pericytes. Tumor vessels display abnormal morphology and increased endothelial proliferation, resulting in leaky, tortuous vessels that are often poorly perfused. These vessels typically display decreased pericyte density, and the tumor-associated pericytes often express abnormal markers and show abnormal morphology. Anti-angiogenic therapy targeting pro-angiogenic growth factor pathways has been applied to a broad range of solid tumors with varying results. Studies utilizing mouse models indicate that the presence of pericytes protect endothelial cells against inhibition of vascular endothelial growth factor (VEGF) signaling. Simultaneous inhibition of PDGF receptors on pericytes therefore improves the effect of VEGF inhibitors on endothelial cells and enhances anti-angiogenic therapy.
C.-H. Heldin (*) Ludwig Institute for Cancer Research, Uppsala University, S-751 24, Uppsala, Sweden e-mail: [email protected]
7.1 Introduction Newly formed capillaries are stabilized through the recruitment of a specialized form of mural cells termed pericytes. In addition to providing physical stabilization, the presence of pericytes reduces endothelial cell proliferation and promotes differentiation, a process termed vascular maturation. During this process, activation of the platelet-derived growth factor (PDGF) b-receptor plays a crucial role in the recruitment of pericytes to the newly formed vessels. In the present communication, we review the role of PDGF in vessel maturation.
7.2 The PDGF Family The PDGF family of growth factors is composed of disulfide-bonded homodimers of four polypeptide chains, the classical PDGF-A and -B chains and the more recently described PDGF-C and -D chains (Fredriksson et al. 2004). In addition, the A and B chains heterodimerize to form PDGF-AB. PDGF isoforms exert their biological effects through the
R. Liersch et al. (eds.), Angiogenesis Inhibition, Recent Results in Cancer Research, DOI: 10.1007/978-3-540-78281-0_7, © Springer Verlag Berlin Heidelberg 2010
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activation of two tyrosine kinase receptors, PDGF a- and b-receptors (Heldin et al. 1998). PDGF family are major mitogens for a number of cell types, including mesenchymal cells such as fibroblasts and smooth muscle cells. During the embryonal development, PDGF isoforms are important for the development of mesenchymal cells of different organs, such as mesangial cells of the kidney, alveolar smooth muscle cells of the lung, smooth muscle cells and pericytes of blood vessels, and glial cells of the central nervous system. Overactivity of PDGF has been linked to atherosclerosis, fibrotic diseases, and malignancies. In certain types of rather rare solid tumo
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