Role of the VEGFC/VEGFR3 pathway, beyond developmental lymphangiogenesis

There are two vascular systems in the body, for blood and lymph, and both are indispensable for embryonic development. The closed circuit of blood vessels is responsible for oxygen and nutrient delivery to all compartments of the body and removal of CO2 and waste products from tissues. The open-ended lymphatic system works as a return route for fluid, immune cells and dietary lipids into the blood circulation. The heart is the central engine for blood flow whereas lymphatic flow is achieved by skeletal and smooth muscle contraction around the lymphatic vessels. Differences between the blood vascular and lymphatic systems are apparent, from the molecular to the functional level. However, the two types of vessels also share a number of signaling molecules and building blocks of vessels. The purpose of the studies presented in this thesis was to expand our knowledge about Vascular Endothelial Growth Factors (VEGFs) and their receptors in development and pathological conditions. In the first study, we found, surprisingly, that VEGFR-3, the receptor for the principal lymphatic vessel growth factor, VEGF-C, is crucial for the normal patterning of the developing blood vessels and that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, leads to excessive blood vessel sprouting and branching. Furthermore, macrophages that express the VEGFR-3 and VEGFR- 2 ligand VEGF-C localized to the vessel branchpoints, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. Our second study focused on the pathological aspect of the atherosclerosis. By using the transgenic mouse that overexpress soluble VEGFR-3 (VEGF-C/D trap) we could link the impaired lymphatic vessels to lipoprotein metabolism, increased plasma cholesterol levels, and enhanced atherogenesis. In the third project we focused on the role of lymphangiogenic growth factors in the steady-state homeostasis of lymphatic vessels in adult mice. Our findings from this study indicated that the lymphangiogenic growth factors provide trophic and dynamic regulation of the intestinal lymphatic vasculature, which could be especially important in the dietary regulation of adiposity and cholesterol metabolism. Finally in the last study we discovered a new role of VEGF-C in the embryonic development. To our surprise, we found a striking VEGF-C dependent phenotype with defective fetal liver erythropoiesis that resulted severe anemia in the Vegfc deteled embryos. These studies have revealed a new viewpoint regarding the VEGF-C/VEGFR-3 pathway in embryonic and pathological conditions. With these results, our understanding of the VEGF family members has expanded beyond the blood and lymphatic vessel. Hopefully, this new knowledge will improve the possibilities to target the VEGF-C/VEGFR-3 pathway for the treatment of human diseases such as atherosclerosis, obesity, and vascular diseases.