Endothelial dysfunction & Cell miscommunication

List of Publications:  

Our research team has identified several major functional alterations in the pulmonary vascular endothelium, including:

Functional alterations in pulmonary vascular endothelium:
  • Pro-proliferative and apoptosis-resistant phenotype
  • Pro-inflammatory phenotype, excessive cytokine and chemokine release
  • Increased expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin)
  • Aberrant pro-proliferative and apoptosis-resistant phenotype
  • Excessive production and secretion of growth factors and TGF-β ligands
  • Dysregulated BMP-9-BMPR-II-Smad1/5/8 and TGF-β-Activin-Smad2/3 signaling pathways
Mechanisms indicating alterations in cell-cell communication:
  • Increased pericyte coverage of pulmonary arteries
  • Dysimmunity dependent on leptin signaling
  • Overabundance of activin contributes to amplifying the accumulation of pulmonary vascular cells in the walls of pulmonary arteries.
Drug-associated PAH:
  • Dasatinib induces endothelial cell dysfunction through increased ROS production
  • Inhibition of endogenous c-Abl leads to loss of genomic integrity in cells and compromises BMPR-II signaling pathway
Therapeutic innovation:
  • 5 prognostic biomarkers for PAH: ß-NGF, CXCL9, TRAIL, activin A, and FSTL3
  • Pre-clinical studies supporting the beneficial effects of innovative drugs:
    • CXCL12/SDF-1 inhibitors
    • Anti-mineralocorticoid molecule Finerenone
    • Pirfenidone
    • Anti-macrophage migration inhibitory factor (MIF)
    • Tryptophan hydroxylase (TPH)-1 inhibitor

 

Publications (Best 10 selected)

  1. Cytokines as Prognostic Biomarkers in Pulmonary Arterial Hypertension. Boucly A, Tu L, Guignabert C, Rhodes C, De Groote P, Prévot G, Bergot E, Bourdin A, Beurnier A, Roche A, Jevnikar M, Jaïs X, Montani D, Wilkins MR, Humbert M, Sitbon O, Savale L. Eur Respir J. 2022
  1. Mineralocorticoid Receptor Antagonism by Finerenone Attenuates Established Pulmonary Hypertension in Rats. Tu L, Thuillet R, Perrot J, Ottaviani M, Ponsardin E, Kolkhof P, Humbert M, Viengchareun S, Lombès M, Guignabert C. Hypertension. 2022
  1. Loss of cAbl Tyrosine Kinase in Pulmonary Arterial Hypertension Causes Dysfunction of Vascular Endothelial Cells. Le Vely B, Phan C, Berrebeh N, Thuillet R, Ottaviani M, Chelgham MK, Chaumais MC, Amazit L, Humbert M, Huertas A, Guignabert C, Tu L. Am J Respir Cell Mol Biol. 2022
  1. Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10. Bouvard C, Tu L, Rossi M, Desroches-Castan A, Berrebeh N, Helfer E, Roelants C, Liu H, Ouarné M, Chaumontel N, Mallet C, Battail C, Bikfalvi A, Humbert M, Savale L, Daubon T, Perret P, Tillet E, Guignabert C*, Bailly S*. Cardiovasc Res. 2022
  1. Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension. Chaumais MC, Djessas MRA, Thuillet R, Cumont A, Tu L, Hebert G, Gaignard P, Huertas A, Savale L, Humbert M, Guignabert C. Cardiovasc Res. 2021
  1. Serum and pulmonary uric acid in pulmonary arterial hypertension. Savale L, Akagi S, Tu L, Cumont A, Thuillet R, Phan C, Le Vely B, Berrebeh N, Huertas A, Jaïs X, Cottin V, Chaouat A, Tromeur C, Boucly A, Jutant EM, Mercier O, Fadel E, Montani D, Sitbon O, Humbert M, Tamura Y, Guignabert C. Eur Respir J. 2021
  1. Lineage Tracing Reveals the Dynamic Contribution of Pericytes to the Blood Vessel Remodeling in Pulmonary Hypertension. Bordenave J, Tu L, Berrebeh N, Thuillet R, Cumont A, Le Vely B, Fadel E, Nadaud S, Savale L, Humbert M, Huertas A, Guignabert C. Arterioscler Thromb Vasc Biol. 2020 
  1. Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension. Tu L, Castan A, Mallet C, Guyon L, Cumont A, Phan C, Robert F, Thuillet R, Bordenave J, Sekine A, Huertas A, Ritvos O, Savale L, Feige JJ, Humbert M, Bailly S, Guignabert C. Circ Res. 2019 

  1. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. Tamura Y, Phan C, Tu L, Le Hiress M, Thuillet R, Jutant EM, Fadel E, Savale L, Huertas A, Humbert M, Guignabert C. J Clin Invest. 2018 

  1. Dasatinib induces lung vascular toxicity and predisposes to PAH. Guignabert C, Phan C, Seferian A, Huertas A, Tu L, Thuillet R, Sattler C, Le Hiress M, Tamura Y, Jutant EM, Chaumais MC, Bouchet S, Manéglier B, Molimard M, Rousselot P, Sitbon O, Simonneau G, Montani D, Humbert M. J Clin Invest. 2016