Lymphatic valves Sample Clauses

Lymphatic valves. Lymphatic valves are essential to prevent the retrograde flow of lymph back into tissue, and indeed patients with lymphedema have been found to have genetic abnormalities in key pathways of lymphatic valve development and maintenance (111). Recent elegant studies in the mouse have elucidated the mechanism of how lymphatic valves form during embryogenesis and in early life (reviewed in (112)). Firstly, there is clustering of LECs at branch points of lymphatic capillaries, which coincides with up- regulation of the transcription factors Prox1 and Foxc2, as well as down-regulation of LYVE-1 expression. These cells then develop an elongated morphology and re-arrange their cell-cell junctions, and eventually form a protrusion into the vessel lumen. This process is dependent on expression of the adhesion molecule receptor, integrin-α9, which allows for proper arrangement of the extracellular matrix at the edges of the LEC protrusions. Mice deficient in integrin-α9 fail to develop fully elongated valve leaflets, and missense mutations in human foetuses causes a lethal phenotype (113). Maturation of the valve is then controlled by various signalling pathways including ephrin B2-eph4 (114), angiopoietin2-Tie2 (115) and phosphoinositide (PI) 3 kinase-protein kinase B (116). Mutations in the PDZ cytoplasmic domain of ephrin B2 result in embryonic lethality characterized by chylothorax due to inhibition of lymphatic drainage into the thoracic duct (102). EphrinB2-eph4 signalling has also been shown to play an essential role in lymphatic and blood vessel angiogenesis. A link between the ephrin B2-eph4 and VEGFR3-VEGF-C pathways was found by Xxxx et al. Stimulation of cultured LECs with recombinant ephrin B2 led to internalisation of VEGFR3, which is required for down- stream signalling, and this process was compromised in ephrin B2 knock-out cells (117).
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