Skip to Main content Skip to Navigation
Journal articles

Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease

Grégoire Manaud 1, 2 Esther Nossent 3 Mélanie Lambert 1, 2 Maria-Rosa Ghigna 4 Angele Boet 4 Maria-Candida Vinhas 4 Benoît Ranchoux 2, 1 Sébastien Dumas 2, 1 Audrey Courboulin 2, 1 Barbara Girerd 2, 1 Florent Soubrier 5, 6 Juliette Bignard 5 Olivier Claude 5 Florence Lecerf 2, 1 Aurélie Hautefort 1, 2 Monica Florio 7 Banghua Sun 7 Sophie Nadaud 5, 6 Stijn Verleden 8 Séverine Remy 9 Ignacio Anegon 9 Harm Jan Bogaard 3 Olaf Mercier 2, 1, 4 Elie Fadel 2, 1, 4 Gerald Simonneau 2, 1 Anton Vonk Noordegraaf 3 Katrien Grünberg 3 Marc Humbert 2, 1 David Montani 10, 2 Peter Dorfmüller 10, 2, 11, 12 Fabrice Antigny 2, 10, 11, 12, * Frédéric Perros 2, 10, 13, * 
Abstract : Pulmonary veno-occlusive disease (PVOD) occurs in humans either as heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2), or as a sporadic form at older age (sPVOD). The chemotherapeutic agent Mitomycin C is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular and molecular levels to unravel common altered pathomechanisms. MMC-exposure in rats was primarily associated with arterial and microvessels remodeling and secondarily followed by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there were convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of heme oxygenase 1 (HO-1) and CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), two downstream effectors of GCN2 signaling and endoplasmic reticulum (ER) stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells (PAECs) using pharmacological and siRNA approaches demonstrated that GCN2 loss-of-function negatively regulates BMP-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced PAECs proliferation. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9 as potential therapeutic options for PVOD.
Document type :
Journal articles
Complete list of metadata

Cited literature [68 references]  Display  Hide  Download
Contributor : Sylvie Le Bihan Connect in order to contact the contributor
Submitted on : Sunday, May 3, 2020 - 12:45:27 PM
Last modification on : Friday, May 20, 2022 - 11:06:51 AM


 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document



Grégoire Manaud, Esther Nossent, Mélanie Lambert, Maria-Rosa Ghigna, Angele Boet, et al.. Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease. American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, 2020, Epub ahead of print. ⟨10.1165/rcmb.2019-0015OC⟩. ⟨inserm-02561102⟩



Record views