CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity

• Published in: The Journal of clinical investigation 2016-06, Vol.126 (6), p.2254-2266
• Main Authors: Crosswhite, Patrick L, Podsiadlowska, Joanna J, Curtis, Carol D, Gao, Siqi, Xia, Lijun, Srinivasan, R Sathish, Griffin, Courtney T
• Format: Article
• Language: English
• Subjects: Animals; Biomedical research; Blood clots; Blood platelets; DNA Helicases - deficiency; DNA Helicases - genetics; DNA Helicases - metabolism; Edema; Enzyme Activation; Extracellular matrix; Female; Fibrinolysin - metabolism; Gene expression; Genetic aspects; Glycoproteins - deficiency; Glycoproteins - genetics; Glycoproteins - metabolism; Health aspects; Helicases; Hemostasis; Hemostasis - genetics; Hemostasis - physiology; Immunoglobulins; Laboratory animals; Liver - blood supply; Liver - embryology; Liver - metabolism; Lymphangiogenesis - genetics; Lymphatic system; Lymphatic Vessels - abnormalities; Lymphatic Vessels - embryology; Lymphatic Vessels - metabolism; Mice; Mice, Knockout; Neovascularization, Physiologic - genetics; Pregnancy; Properties; Proteins; Receptors, Urokinase Plasminogen Activator - genetics; Receptors, Urokinase Plasminogen Activator - metabolism; Rodents; Up-Regulation; Weaning
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci84652

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.