Fig. 3

The schematic diagram of embryonic lymphatic vessel development. a Beginning at E9.5, VeECs, located at CV and ISVs, transdifferentiate into LEPCs. During E10.5-E15.5, the lymphatic plexus continues to sprouting and migrating, and expanding the primary lymphatic vessel network. Continuing from E15.5 until the early postnatal stage, the primary lymphatic plexus undergoes the maturation events to remodel into the hierarchical lymphatic vessels, comprising of capillary lymphatic vessels, pre-collecting lymphatic vessels, and collecting lymphatic vessels. Capillary lymphatic vessels sense interstitial pressure changes by anchoring filaments to control the opening of button-like junctions. The formation of pre-collecting and collecting lymphatic vessels requires for lymphatic valves morphogenesis and SMCs recruitment to drive lymph drainage; b At E10.5, upregulated VEGFR3 and NRP2 mediate LEPCs sprouting and LECs migration in response to VEGFC stimulation. VEGFC/VEGFR3 is an irreplaceable signaling regulates lymphatic vessel development; c The lymphovenous valve serves as the only connection of the lymphatic-venous system to prevent blood backflow. Platelet dynamically regulated lymphovenous hemostasis via interacting with LECs to activate CLEC2/PDPN signaling pathway to maintain platelet aggregation; d Under the stimulation of OSS, the differentiation of valve-forming cells prepares to proliferation, elongation, and protrusion. Moreover, ECM deposition and selective SMCs coverage further promote lymphatic vessel maturation. Ex embryonic day x, VeECs venous endothelial cells, CV cardinal vessel, ISVs intersomitic veins, LECs lymphatic endothelial cells, LEPCs lymphatic endothelial progenitor cells, VEGFC vascular endothelial growth factor C, VEGFR3 vascular endothelial growth factor receptor 3, NRP1/2 neuropilin 1/2, CLEC2 c-type lectin-like receptor 2, PDPN podoplanin, OSS oscillatory shear stress, MCP1 monocyte chemotactic protein 1, PDGFB platelet-derived growth factor B, ECM extracellular matrix, SMCs smooth muscle cells. Created with Adobe Illustrator