| First Author | Crosswhite PL | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 6 | Pages | 2254-66 |
| PubMed ID | 27140400 | Mgi Jnum | J:237076 |
| Mgi Id | MGI:5810841 | Doi | 10.1172/JCI84652 |
| Citation | Crosswhite PL, et al. (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest 126(6):2254-66 |
| abstractText | 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. |
