CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity
Identifieur interne : 012E82 ( Main/Exploration ); précédent : 012E81; suivant : 012E83CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity
Auteurs : Patrick L. Crosswhite [États-Unis] ; Joanna J. Podsiadlowska [États-Unis] ; Carol D. Curtis [États-Unis] ; Siqi Gao [États-Unis] ; Lijun Xia [États-Unis] ; R. Sathish Srinivasan [États-Unis] ; Courtney T. Griffin [États-Unis]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; ????.
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
Url:
DOI: 10.1172/JCI84652
PubMed: 27140400
PubMed Central: 4887170
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>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 <italic>Chd4</italic>
specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. <italic>Chd4</italic>
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 (<italic>uPAR</italic>
), which facilitates activation of the fibrin-degrading protease plasmin, were upregulated in <italic>Chd4</italic>
mutant LYVE1<sup>+</sup>
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 <italic>Chd4</italic>
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.</p>
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<name sortKey="Curtis, Carol D" sort="Curtis, Carol D" uniqKey="Curtis C" first="Carol D." last="Curtis">Carol D. Curtis</name>
<name sortKey="Gao, Siqi" sort="Gao, Siqi" uniqKey="Gao S" first="Siqi" last="Gao">Siqi Gao</name>
<name sortKey="Griffin, Courtney T" sort="Griffin, Courtney T" uniqKey="Griffin C" first="Courtney T." last="Griffin">Courtney T. Griffin</name>
<name sortKey="Griffin, Courtney T" sort="Griffin, Courtney T" uniqKey="Griffin C" first="Courtney T." last="Griffin">Courtney T. Griffin</name>
<name sortKey="Podsiadlowska, Joanna J" sort="Podsiadlowska, Joanna J" uniqKey="Podsiadlowska J" first="Joanna J." last="Podsiadlowska">Joanna J. Podsiadlowska</name>
<name sortKey="Srinivasan, R Sathish" sort="Srinivasan, R Sathish" uniqKey="Srinivasan R" first="R. Sathish" last="Srinivasan">R. Sathish Srinivasan</name>
<name sortKey="Srinivasan, R Sathish" sort="Srinivasan, R Sathish" uniqKey="Srinivasan R" first="R. Sathish" last="Srinivasan">R. Sathish Srinivasan</name>
<name sortKey="Xia, Lijun" sort="Xia, Lijun" uniqKey="Xia L" first="Lijun" last="Xia">Lijun Xia</name>
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