Signaling pathways in lymphatic vessels. Lymphatic sprouting and proliferation is regulated by a variety of external stimuli and intracellular signaling pathways. Loss of Vegf-c/Vegfr-3 or Ccbe1 completely prevents formation of lymphatic vessels, demonstrating a central role in lymphangiogenesis. Nrp2 and EphrinB2 enhance VEGF-C-dependent lymphangiogenic sprouting and signaling. Vegfr-2 also contributes to lymphangiogenic response. TGFβ/BMP and angiopoietin-2 are important both for lymphatic capillary patterning and maturation of collecting lymphatic vessels. Dll4/Notch signaling restricts LEC response to Vegf-a in adult tissues, whereas it has a prolymphangiogenic function during postnatal development. The Ras-RAF-mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway promotes lymphatic endothelial proliferation, likely downstream of VEGFR-3. Class I PI3 kinases are required for growth and remodeling of lymphatic vasculature in some vascular beds. Although strongly activated by (lymph)angiogenic growth factors in LECs in vitro, in vivo, the Ca²⁺/calcineurin pathway is mostly implicated in lymphatic collecting vessel development, in cooperation with Foxc2. Some pathways are also important for establishment of lymphatic endothelial cell identity, such as Notch and Raf/MEK/ERK1/2. Blue boxes indicate pathways also involved in sprouting. Foxc2 and calcineurin/Nfatc1 cooperatively regulate collecting vessel maturation (green box).