Abstract
Liver dysfunction is a major problem in patients with severe preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or in patients receiving anti-vascular endothelial growth factor (VEGF) therapy. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antagonizes VEGF has been implicated in the pathogenesis of PE. VEGF increases the expression of endothelial nitric oxide synthase (eNOS) and activates it. eNOS polymorphisms that cause reduced NO production are associated with PE. The aim of this study was to clarify the role on hepatic function by excess sFlt1 in the absence of eNOS gene product. We first overexpressed sFlt1 using adenovirus in eNOS−/− and eNOS+/+ mice. Excessive sFlt1 and lack of eNOS synergistically increased plasma levels of liver transaminases, exacerbated infiltration of inflammatory cells, elevated expression levels of cytokines in the liver, and aggravated oxidative stress and coagulation abnormalities. Lack of eNOS in the presence of excess sFlt1 also induced thrombocytopenia, whereas eNOS+/+ mice with excess sFlt1 alone showed no or modest liver phenotype. Taken together, excessive sFlt1 and lack of eNOS synergistically induce hepatic dysfunction and thrombocytopenia, suggesting a novel role for VEGF and nitric oxide signaling in hepatocyte-endothelial cross-talk in health and in liver injury states.
Highlights
Vascular endothelial growth factor (VEGF) is indispensable in the maturation and maintenance of endothelial cells[1]
We have demonstrated that the lack of endothelial nitric oxide synthase (eNOS) in the presence of excessive sFlt[1] exacerbates hepatic injury and causes hypercoagulability and thrombocytopenia
Our data show that the livers from the eNOS−/−; sFlt[1] mice have enhanced hepatic inflammation, prominent neutrophil infiltration, and increased oxidative stress and the expression of genes induced by hypoxia
Summary
Vascular endothelial growth factor (VEGF) is indispensable in the maturation and maintenance of endothelial cells[1]. Some investigators showed that knocking down hepatic VEGF or excessive sFlt[1] causes hepatotoxicity[2,9], whereas others have demonstrated VEGF inhibitors do not affect liver function[10]. These findings may indicate that additional factor(s) may be required for VEGF inhibitors to induce liver dysfunction. Demonstrated that lack of eNOS exacerbates sFlt1-induced kidney injury through endothelin activation[15] Based on these findings, we hypothesized that eNOS dysfunction is likely involved in the exacerbation of tissue injury caused by VEGF inhibition.
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