{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Crosswhite PL"],"funding":["NICHD NIH HHS","NHLBI NIH HHS"],"pagination":["2254-66"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4887170"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["126(6)"],"pubmed_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."],"journal":["The Journal of clinical investigation"],"pubmed_title":["CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity."],"pmcid":["PMC4887170"],"funding_grant_id":["P01 HL085607","R01 HL111178","R01 HD083418"],"pubmed_authors":["Srinivasan RS","Curtis CD","Xia L","Griffin CT","Podsiadlowska JJ","Crosswhite PL","Gao S"],"additional_accession":[]},"is_claimable":false,"name":"CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity.","description":"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.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Jun","modification":"2021-02-20T17:43:43Z","creation":"2019-03-27T02:14:54Z"},"accession":"S-EPMC4887170","cross_references":{"pubmed":["27140400"],"doi":["10.1172/jci84652","10.1172/JCI84652"]}}