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BMP9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and protecting from hepatic fibrosis

Abstract : Bone morphogenetic protein 9 (BMP9) is a circulating factor produced by hepatic stellate cells that plays a critical role in vascular quiescence via its endothelial receptor ALK1. Mutations in the gene encoding ALK1 cause HHT2 (Hereditary Hemoragic Telangiectasia type 2), a rare genetic disease presenting hepatic vessel malformations. Variations of both the circulating levels and the hepatic mRNA levels of BMP9 have been recently associated with various forms of hepatic fibrosis. However, the molecular mechanism that links BMP9 with liver diseases is still unknown. Here, we report that Bmp9 gene deletion in 129/Ola mice triggers hepatic perisinusoidal fibrosis that was detectable from 15 weeks of age. An inflammatory response appeared within the same time frame as fibrosis, whereas sinusoidal vessel dilation developed later on. Proteomic and mRNA analyses of primary liver sinusoidal endothelial cells (LSECs) both revealed that the expression of the LSEC-specifying transcription factor GATA4 was strongly reduced in Bmp9-KO mice as compared to wild type mice. LSECs from Bmp9-KO mice also lost the expression of several terminal differentiation markers (Lyve1, Stab1, Stab2, Ehd3, Cd209b, eNos, Maf, Plvap). They gained CD34 expression and deposited a basal lamina, indicating that they were capillarized. Another main characteristic of differentiated LSECs is the presence of permeable fenestrae. LSECs from Bmp9-KO mice had a significantly reduced number of fenestrae. This was already observable in 2-week-old pups. Moreover, we could show that addition of BMP9 to primary cultures of LSECs prevented the loss of their fenestrae and maintained the expression levels of Gata4 and Plvap. Taken together, our observations show that BMP9 is a key paracrine regulator of liver homeostasis, controlling LSEC fenestration and protecting from perivascular hepatic fibrosis. This article is protected by copyright. All rights reserved.
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https://hal.univ-grenoble-alpes.fr/hal-02101345
Contributeur : Jean-Jacques Feige <>
Soumis le : mardi 16 avril 2019 - 16:12:37
Dernière modification le : lundi 20 juillet 2020 - 11:42:03

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Agnès Desroches-Castan, Emmanuelle Tillet, Nicolas Ricard, Marie Ouarné, Christine Mallet, et al.. BMP9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and protecting from hepatic fibrosis. Hepatology, Wiley-Blackwell, 2019, ⟨10.1002/hep.30655⟩. ⟨hal-02101345⟩

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