VEGFR signaling during lymphatic vascular development: From progenitor cells to functional vessels.
Lymphatic vessels are an integral component of the cardiovascular system, serving important roles in fluid homeostasis, lipid absorption, and immune cell trafficking. Defining the mechanisms by which the lymphatic vasculature is constructed and remodeled into a functional vascular network not only provides answers to fascinating biological questions, but is fundamental to understanding how lymphatic vessel growth and development goes awry in human pathologies. While long recognized as dysfunctional in lymphedema and exploited as a route of tumor metastasis, recent work has highlighted important roles for lymphatic vessels in modulating immune responses, regulating salt-sensitive hypertension and important for lung inflation at birth. Substantial progress in our understanding of the signaling pathways important for development and morphogenesis of the lymphatic vasculature has been made in recent years. Here, we review advances in our knowledge of the best characterized of these signaling pathways, that involving the vascular endothelial growth factor (VEGF) family members VEGF-C and VEGF-D, together with their receptors VEGFR2 and VEGFR3. Recent work has defined multiple levels at which signal transduction by means of this key axis is regulated; these include control of ligand processing and bioavailability, modulation of receptor activation by interacting proteins, and regulation of receptor endocytosis and trafficking.
Centre for Cancer Biology, University of South Australia, and SA Pathology, Adelaide, Australia.
Genevieve A
GA
Secker
Natasha L
NL
Harvey
D000818:Animals; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000166:cytology / Q000196:embryology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; C581309:FLT4 protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
VEGF-C; VEGF-D; VEGFR2; VEGFR3; lymphangiogenesis; signal transduction; vascular endothelial growth factor (VEGF)