Abstract 1123: The Functional Roles Of Cxcr4 In Lymphangiogenesis

Introduction: The lymphatic vessels play important roles in maintaining tissue fluid homeostasis, intestinal lipid uptake and immune surveillance. Malformation or dysfunction of these vessels are associated with a number of diseases, including lymphedema, inflammation, fibrosis, myocardial infarction and atherosclerosis etc. Recent studies have shown that stimulation of lymphatic vessel growth could prevent lymphedema and improve many disease pathologies, highlighting targeting lymphatic growth as a novel therapeutic approach for lymphatic related disease. Hypothesis: Lymphatic vessels grow by active sprouting, and subsequently mature into a vascular complex including lymphatic capillaries and collecting vessels that ensure fluid transport. However, the mechanisms regulate lymphatic sprouting and patterning are largely unknown. Here we have identified one of the key regulators and signaling pathways involved in lymphangiogenesis and function during development and disease especially CXCL12(SDF-1)/Cxcr4, a novel chemokine signaling, that plays critical roles in regulating lymphatic sprouting and morphogenesis during development. Results: We showed that Cxcr4 is highly expressed in migrating and sprouting lymphatic endothelial cells (LECs) during early embryonic stages. Importantly, LEC specific CXCR4 deficient embryos develop severe edema, with impaired lymphatic sprouting and migration. In addition, LEC specific Cxcr4 deficient embryos show reduced cell surface VEGFR3 but increased intracellular VEGFR3 levels in lymphatic vessels.In vitro studies showed that the blockade of Cxcr4 activity affects VEGFC-mediated LEC function. SDF-1 treatment stimulated LEC sprouting, migration and tube formation, and these effects were greatly inhibited by AMD3100 treatment which is Cxcr4 antagonist. Conclusions: These data suggest Cxcr4 has a novel role in regulating lymphangiogenesis, and identifying the molecular mechanism that pave the way for novel therapeutic strategies in lymphatic related disorders and cardiovascular diseases.