title: CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity.
abstract: The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of Chd4 specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. Chd4 mutant embryos died before birth and exhibited severe edema, blood-filled lymphatics, and liver hemorrhage. CHD4-deficient embryos developed normal lymphovenous (LV) valves, which regulate the return of lymph to the blood circulation; however, these valves lacked the fibrin-rich thrombi that prevent blood from entering the lymphatic system. Transcripts of the urokinase plasminogen activator receptor (uPAR), which facilitates activation of the fibrin-degrading protease plasmin, were upregulated in Chd4 mutant LYVE1+ cells, and plasmin activity was elevated near the LV valves. Genetic reduction of the uPAR ligand urokinase prevented degradation of fibrin-rich thrombi at the LV valves and largely resolved the blood-filled lymphatics in Chd4 mutants. Urokinase reduction also ameliorated liver hemorrhage and prolonged embryonic survival by reducing plasmin-mediated extracellular matrix degradation around sinusoidal blood vessels. These results highlight the susceptibility of LV thrombi and liver sinusoidal vessels to plasmin-mediated damage and demonstrate the importance of CHD4 in regulating embryonic plasmin activation after mid-gestation.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Crosswhite
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Podsiadlowska
authors.forename: Carol D
authors.initials: CD
authors.lastname: Curtis
authors.forename: Siqi
authors.initials: S
authors.lastname: Gao
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: R Sathish
authors.initials: RS
authors.lastname: Srinivasan
authors.forename: Courtney T
authors.initials: CT
authors.lastname: Griffin
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006487:Hemostasis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000098:blood supply* / Q000196:embryology* / Q000378:metabolism; D042583:Lymphangiogenesis / Q000235:genetics; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D011247:Pregnancy; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D004265:DNA Helicases; D005341:Fibrinolysin; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D055293:Receptors, Urokinase Plasminogen Activator; C524899:Plaur protein, mouse; C492273:LYVE1 protein, mouse; C509277:Mi-2beta protein, mouse