Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins

Abstract

Lymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development.

Interaction of tumor cells and lymphatic vessels in cancer progression

“…4 This budding and migration of lymphatic endothelial progenitor cells is mediated by VEGF-C signals and is critically modulated by collagen-and calcium-binding EGF domain 1 protein. 6,7 COUP-TFII and Prox-1 are essential for the maintenance of the identity of the lymphatic endothelial cells following their differentiation. 8 The primary lymphatic networks then enlarge by sprouting lymphangiogenesis induced by the VEGFR-3 ligand VEGF-C. By upregulation of VEGFR-3 expression independently of Prox-1, T-box transcription factor 1 supports the growth and maintenance of the gastrointestinal lymphatic vessel network.…”

Lymphangiogenesis by blind‐ended vessel sprouting is concurrent with hemangiogenesis by vascular splitting

“…Recently, regulators were also pipetted directly onto the early chicken CAM at E5 (Melkonian et al, 2002), and CAM assays were reviewed in thorough helpful detail (Richardson and Singh, 2003). In avian and mammalian embryos, it is becoming clear that lymphangiogenesis follows earlier development of the blood vascular system in a complex, rather intertwined fashion (Wigle and Oliver, 1999;Karkkainen et al, 2004;Wilting et al, 2004).…”

Development of the lymphatic vascular system: A mystery unravels

“…Although the expression of Prox1 in the lymphatically specified venous endothelial cells of the cardinal vein was not inhibited in VEGF-C-deficient mice, Prox1-positive cells were unable to migrate out to form the initial lymph sacs, indicating that lymphatic endothelial cell specification and subsequent cell migration are two separate events, possibly controlled by distinct signaling pathways. Importantly, the sprouting defect of the committed LEC progenitors was rescued by application of VEGF-C or VEGF-D, but not VEGF-A, indicating the necessity of VEGFR-3-mediated signaling for the initial lymphatic vessel formation (Karkkainen et al, 2004). Because VEGFR-3 is expressed by all venous endothelial cells at mouse E8.5, additional autocrine or paracrine signals likely induce lymphatic cell fate among the VEGFR-3-positive cells by activating Prox1 expression.…”

“…VEGF-C is expressed by a multitude of cell types, including mesenchymal cells around embryonic veins, activated macrophages, skeletal muscle cells, and smooth muscle cells surrounding large arteries Kukk et al, 1996;Eichmann et al, 1998;Karkkainen et al, 2004). Of interest, blood vascular endothelial cells also express VEGF-C , suggesting possible paracrine mechanisms by which the blood vascular system may control lymphatic vessel growth and/or maintenance.…”

“…VEGF-C plays an essential role during embryonic lymphangiogenesis, as revealed by the phenotype of VEGF-C-deficient mice (Karkkainen et al, 2004). Whereas VEGF-C was not required for the normal development of the blood vascular system, the early lymphatic vessel formation was completely abrogated.…”