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CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity
Patrick L. Crosswhite, … , R. Sathish Srinivasan, Courtney T. Griffin
Patrick L. Crosswhite, … , R. Sathish Srinivasan, Courtney T. Griffin
Published May 3, 2016
Citation Information: J Clin Invest. 2016;126(6):2254-2266. https://doi.org/10.1172/JCI84652.
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Research Article Vascular biology Article has an altmetric score of 56

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

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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

Patrick L. Crosswhite, Joanna J. Podsiadlowska, Carol D. Curtis, Siqi Gao, Lijun Xia, R. Sathish Srinivasan, Courtney T. Griffin

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Figure 1

Chd4fl/fl VE-cadherin-Cre+ and Chd4fl/fl Lyve1-Cre+ embryos display edema and blood-filled lymphatics before death.

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Chd4fl/fl VE-cadherin-Cre+ and Chd4fl/fl Lyve1-Cre+ embryos display ede...
(A-F) Littermate control (A–C) and Chd4fl/fl VE-cadherin-Cre+ (D–F) embryos were photographed from E14.5 to E16.5. n = 10 embryos per genotype per time point. Mutants displayed edema (white arrows) and prominent superficial blood-filled vessels (white arrowheads) as early as E14.5 and died by E16.5. (G–J) Sections from E14.5 control (G and H) and Chd4fl/fl VE-cadherin-Cre+ (I and J) embryos were immunostained for the red blood cell marker Ter119 (red) and the lymphatic marker LYVE1 (green), and nuclei were counterstained with Hoechst (blue). The Chd4fl/fl VE-cadherin-Cre+ embryos had enlarged, blood-filled jugular lymph sacs (JLS; I, white arrow) and dermal lymphatic vessels (DLV; J, white arrow). n = 3 embryos per genotype. (K–P) Littermate control (K–M) and Chd4fl/fl Lyve1-Cre+ (N–P) embryos were photographed from E13.5 to E14.5. Mutants displayed edema (white arrows) as early as E13.5 and superficial blood-filled vessels (white arrowheads) by early E14.5, and died by late E14.5. n = 10 embryos per genotype per time point. (Q and R) Sections from E14.5 control (Q) and Chd4fl/fl Lyve1-Cre+ (R) embryos were immunostained for LYVE1 (red), CHD4 (green), and Hoechst (blue) to assess CHD4 expression in LECs (white arrows). Insets show 5× magnified images of LECs in boxed regions. n = 3 embryos per genotype. (S and T) Sections from late E14.5 control (S) and Chd4fl/fl Lyve1-Cre+ (T) embryos were stained with H&E. Red blood cells (black arrows) were detected in the enlarged jugular lymph sac (JLS) of mutant embryos. n = 3 embryos per genotype. For A–F and K–P, embryos at each time point were imaged at the same magnification. Scale bars: 100 μm (G–J, S, and T); 50 μm (Q and R). JV, jugular vein; CA, carotid artery.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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