title: Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function.
abstract: The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA Rachel.Rothflach@pfizer.com Michael.Czech@umassmed.edu.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Chang-An
authors.initials: CA
authors.lastname: Guo
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Danai
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Yawe
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Sharvari
authors.initials: S
authors.lastname: Gujja
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Yvonne J K
authors.initials: YJ
authors.lastname: Edwards
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA Rachel.Rothflach@pfizer.com Michael.Czech@umassmed.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D049109:Cell Proliferation; D002916:Chylothorax / Q000235:genetics / Q000401:mortality*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D042601:Lymphatic Vessels / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C117090:MAP4K4 protein, human