Mechanisms of lymphangiogenesis Sample Clauses

Mechanisms of lymphangiogenesis. The VEGF-C/D and VEGFR3 pathway is the central pathway in lymphangiogenesis (144). As mentioned previously, VEGFC/VEGFR3 signalling is essential for lymphatic sprouting from the cardinal vein in embryogenesis (145). Activation of VEGFR3 leads to phosphorylation of the serine kinases AKT and extracellular signal-related kinase (ERK), which promotes proliferation, migration and survival of LECs (146). PI3K, which is upstream of AKT, interacts directly with VEGFR3 and promotes tube formation (147). Interestingly, defects in the PI3K pathway affect lymphatic vasculature only and have no effect on blood vessels; suggesting that AKT functions distinctively in LECs. The congenital primary lymphedema condition Xxxxxx’x disease is caused by missense mutations in the tyrosine kinase domain of VEGFR3 (105). The VEGF and VEGFR2 pathway plays less of a role in lymphangiogenesis than the VEGFC/VEGFR3 pathway. Specific activation of this pathway causes vessel enlargement but does not initiate sprouting (148), and deletion of the VEGFR2 gene in LECs does not affect lymphatic vessel function in embryogenesis and adult mice (149). There are also data to show that the Notch pathway plays a role in VEGF/VEGFR2- induced lymphangiogenesis. It was found that lymphangiogenesis occurring via this pathway was enhanced when the Notch pathway was inhibited; and this was not seen in VEGFC/VEGFR3-induced lymphangiogenesis (150). The collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) is a highly conserved lymphagiogenic factor, and the result of deletion of this protein is similar to VEGFC deletion, with embryos not forming lymphatic vessels (151). Mutations in the CCBE1 gene in humans cause primary lymphedema in Henneken’s syndrome (152). Exogenous CCBE1 has little effect on inducing lymphangiogenesis, but seems to interact with the VEGFC pathway (153). Semaphorins and neuropilins have traditionally been described for their pivotal role in the central nervous system; however, they are now becoming recognised in the field of lymphangiogenesis. Neuropilin (NRP) 2 is a co-receptor for VEGFC and binding causes co-internalization of the two receptors which enhances VEGFC signalling (154). NRP2- deficient mice have normal blood vasculature but decreased density of lymphatic capillaries in tissue (155). The NRP1 ligand semaphorin (SEMA) 3A is highly expressed in LECs and is particularly involved in lymphatic valve formation, where it has been shown to facilitate the migratio...
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