314 K.-H. Thierauch & A. Chlistalla

The effect of these factors may be anti-angiogenic or pro-angiogenic. Many of those receptors have a kinase function which are activated by extracellular binding of a ligand and transmit the signal intracellularly via an activation cascade which contains several kinases itself. Therefore, inhibition of any of those kinases may fall under the paradigm of angiogenesis inhibition especially, as proliferating endothelial cells are relatively sensitive to the toxic action of non-specific kinase inhibitors. Many of these kinases have been described as oncogenes involved in tumorigenesis and are potential targets of tumor cell-directed therapy. Some kinases may activate receptor tyrosine phosphatases so their inhibition can be considered as pro-angiogenic.

2. Major Angiogenesis Factors and Receptors

2.1. VEGF signaling

In a stricter sense, only kinases which are essential and specific for endothelial cells, or the interaction with them, should be considered as anti-angiogenesis targets. Endothelium-specific kinases, which play a major role in angiogenesis are VEGFR-1, -2 and -3 and Tie1 and - 2. VEGFR-2 is considered to play a pivotal role in angiogenesis and is almost exclusively located on the surface of endothelial cells. The inhibition of its kinase function leads to an inhibition of cell proliferation and migration.6,7 Important exceptions, where other functions are assumed, are found in kidney glomeruli,8 on hematopoietic stem cell precursors9 and in a neural stem cell population.10 Stimulators of VEGFR-2 are the known splice variants of VEGF-A,11 VEGF-C (processed form12) and VEGF-D (processed form13). VEGFR-1, which is an indispensable co-receptor of VEGFR-2, also binds to VEGF-B and PlGF.14 This receptor is found on peripheral blood monocytic cells (PBMC), where it plays a role in monocyte migration and tissue factor expression.14,15 VEGFR-3, which transduces a signal for lymphangiogenesis, is activated by VEGF-C and VEGF-D.12

Other binding proteins for VEGF-A on the surface of endothlial cells are neuropilin-1 and -2.16,17 At the C-terminus of the neuropilins, there is a short intracellular peptide chain, which makes a direct signaling into the endothelial cell improbable. In addition to VEGF, neuropilins bind