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

Crosswhite, Patrick; Podsiadlowska, Joanna J.; Curtis, Carol D.; Gao, Siqi; Xia, Lijun; Srinivasan, Ramesh; Griffin, Courtney T.

doi:10.1172/jci84652

Cited by 29 publications

(36 citation statements)

References 51 publications

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“…LYVE-1 protein is robustly expressed by LECs during normal mouse development, including in the jugular lymph sacs at E12.5, and is also detected at some level in lymph nodes, liver sinusoids, spleen sinuses, blood vessels, endocardium and a subpopulation of macrophages (Banerji et al, 1999; Baluk and McDonald, 2008; Gordon et al, 2008). The Lyve-1 Cre mouse line has been used by others to successfully inactivate, in a lymphatic-targeted manner, the genes encoding sphingosine kinase, VEGFR2, and the chromatin remodeling enzyme CHD4 (Pham et al, 2010; Dellinger et al, 2013; Crosswhite et al, 2016). Dellinger et al showed that Lyve-1 Cre can be used to delete floxed DNA sequences in LECs that generate collecting lymphatics and their valves, as well as lymphatic capillaries (Dellinger et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

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Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Munger

Davis

Simon

2017

Developmental Biology

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Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43−/− mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43ΔLEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

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Section: Resultsmentioning

confidence: 99%

“…Using the same Lyve-1 Cre allele, Crosswhite et. al showed that CHD4 is efficiently deleted from Lyve-1 Cre ; Chd4 fl/fl LECs by E14.5 (Crosswhite et al, 2016). LV formation in the mesenteric collecting lymphatics, which are derived from the LYVE-1 positive lymphatic capillaries, does not begin until E16.…”

Section: Discussionmentioning

confidence: 99%

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Munger

Davis

Simon

2017

Developmental Biology

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“…Similar to STAB2, LYVE1 shows restricted vascular expression in LSECs, but LYVE1 is also known to be expressed by lymphatic endothelium as well as by HSCs and progenitor cells and by some macrophage populations (28). In Lyve1-Cre R26LacZ reporter mice, β-gal activity was predominantly found in LSECs (Supplemental Figure 5A).…”

Section: Genetic Inactivation Of Gata4 In the Hepatic Microvasculaturmentioning

confidence: 95%

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

Géraud¹,

Koch²,

Zierow³

et al. 2017

Journal of Clinical Investigation

121

143

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“…We previously reported that excessive plasmin activation and subsequent ECM degradation cause embryonic vascular fragility . Embryonic hepatic sinusoidal blood vessels are particularly prone to rupture when their underlying laminin‐rich ECM is degraded by plasmin .…”

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confidence: 99%

Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

et al. 2018

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The serine protease plasmin degrades extracellular matrix (ECM) components both directly and indirectly through activation of matrix metalloproteinases. Excessive plasmin activity and subsequent ECM degradation cause hepatic sinusoidal fragility and hemorrhage in developing embryos. We report here that excessive plasmin activity in a murine acetaminophen (APAP) overdose model likewise compromises hepatic sinusoidal vascular integrity in adult animals. We found that hepatic plasmin activity is up-regulated significantly at 6 hours after APAP overdose. This plasmin up-regulation precedes both degradation of the ECM component fibronectin around liver vasculature and bleeding from centrilobular sinusoids. Importantly, administration of the pharmacological plasmin inhibitor tranexamic acid or genetic reduction of plasminogen, the circulating zymogen of plasmin, ameliorates APAP-induced hepatic fibronectin degradation and sinusoidal bleeding. Conclusion: These studies demonstrate that reduction of plasmin stabilizes hepatic sinusoidal vascular integrity after APAP overdose. (Hepatology 2018; 00:1-13).

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

Cited by 29 publications

References 51 publications

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

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