Abstract
The endothelial cells of the blood and lymphatic vessels are involved in common human diseases. Excess blood and lymphatic vessel growth enhances tumor progression and metastasis, whereas insufficient growth leads to tissue ischemia and lymphedema. Lymphatic and blood vascular endothelial cells are regulated by two endothelial specific receptor tyrosine kinase systems, the vascular endothelial growth factor (VEGF) receptors (VEGFRs) and the Tie receptors, activated by the VEGF and angiopoietin ligands, respectively. Blocking of the VEGF-VEGFR-2 pathway has provided the first antiangiogenic strategy for cancer therapy and here we discuss the other pathways where progress is made for drug development, in particular the angiopoietin (Ang)-Tie receptor pathway. VEGF-activated VEGFR-2 is the major transducer of angiogenic signals, but recent results show that the lymphangiogenic VEGFR-3 induces angiogenic sprouting as well. VEGF-B, a member of the VEGF family with low angiogenic activity, has been found to be involved in the regulation of energy metabolism in the heart. Recent reports have implicated Ang2 in tumor angiogenesis and revealed that Tie2 utilizes a unique signaling mechanism at endothelial cell-cell junctions. The VEGF-VEGFR and Ang-Tie systems regulate different aspects of blood and lymphatic vessel growth. Thus, targeting both systems may be beneficial in maximizing the efficacy of anti/pro-angiogenic therapies.
Published Version
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