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Georg Breier
Mechanisms of blood vessel development and tumor angiogenesis
Previous and current research
Vascular endothelial cells form the inner lining of all blood vessels and play a critical role in various physiological and pathological processes, including embryogenesis, tumor growth, diabetic retinopathy, and wound healing. My group is studying the cell biology and genetics of blood vessel formation and remodeling, both in the mouse embryo and in tumors. Specifically, we are trying to understand how endothelial signalling systems and transcriptional regulators control the function of endothelial cells and their interaction with the surrounding tissue.
Our previous studies have contributed to the identification of vascular endothelial growth factor (VEGF) as a key regulator of early stage vascular development. VEGF has also an essential function in brain angiogenesis and development, by stimulating the sprouting of capillaries, by guiding their growth in the neural tissue, and possibly also by acting directly on neural cells. We have also studied endothelial cell intrinsic regulatory mechanisms of endothelial growth and differentiation. Our data support a model in which vascular development and angiogenesis is controlled by the combinatorial activity of members of the Ets family of transcription factors and by hypoxia-inducible factors (HIF). Many regulatory pathways that control physiological angiogenesis are also active in tumors and represent therefore potential targets for therapeutic intervention.
Future prospects and goals
The development of the vascular system is intimately linked with the differentiation of organs and tissues. In the future, we will try to understand how endothelial signalling systems coordinate the interaction between vascular endothelial cells and neural tissue. Transgenic and knockout animals in which the expression of these proteins is altered will be used to study the function of these signalling systems in vivo. Likewise, we will study the function of HIF family members and of other proteins involved in oxygen sensing, in endothelial cell differentiation, degeneration, regeneration and function.
About
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Selected publications
Licht AH, Muller-Holtkamp F, Flamme I, Breier G (2006): Inhibition of hypoxia-inducible factor activity in endothelial cells disrupts embryonic cardiovascular development. Blood 107: 584-590.
Mitola S, Brenchio B, Piccinini M, Tertoolen L, Zammataro L, Breier G, Rinaudo MT, den Hertog J, Arese M, Bussolino F (2006): Type I Collagen limits VEGFR-2 signaling by a SHP2 protein-tyrosine phosphatase-dependent mechanism. Circ Res 98:45-54.
Raab S, Beck H, Gauman A, Yuce A, Gerber HP, Plate KH, Hammes HP, Ferrara N, Breier G (2004): Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost 91: 595-605.
Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate KH, Siewecke M, Breier G, Flamme I (2003): Cooperative interaction of hypoxia-inducible factor-2a and Ets-1 in the transcriptional activation of Flk-1. J Biol Chem 278: 7520-7530.
Vajkoczy P, Farhadi M, Gaumann A, Heidenreich R, Erber R, Wunder A, Tonn JC, Menger MD, and Breier G (2002): Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF-receptor-2, and angiopoietin-2. J Clin Invest 109: 777-785.
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declerq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996): Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435-439.