Endothelial dysfunction & Cell miscommunication

List of Publications:  

Our research team has already highlighted several major functional alterations in the pulmonary vascular endothelium:

Intrinsic altered phenotype:

  • a transition from a quiescent state to an activated state with adhesive capacity;
  • an aberrant pro-proliferative and apoptosis-resistant phenotype;
  • a pro-inflammatory phenotype characterized by an excessive release of various key cytokines and chemokines: interleukin (IL)-1α, IL-6, IL-8, IL-12, CCL2, monocyte chemotactic protein (MCP)-1;
  • an excessive production and secretion of various key growth factors including fibroblast growth factor-2 (FGF-2; basic FGF) angiotensin-II (Ang II), and leptin (Ob);
  • dysregulated BMPR2/BMP9 signaling pathways

Cell miscommunication

  • increased pericyte coverage of pulmonary arteries, an abnormality that is a potential source of smooth muscle–like cells involved in the pulmonary vascular remodelling;
  • dysimmunity leptin-dependent;
  • dysregulation of Type I cytokine receptors on pulmonary artery smooth muscle cells

Drug-induced PAH:

  • the role of dasatinib in inducing endothelial cell dysfunction via increased production of reactive oxygen species (ROS), a phenomenon that can partly explain dasatinib-related pleural effusion as well as the increase susceptibility to PAH development

 

Therapeutic innovation

Our group is also leading pre-clinical studies on the effects of innovative therapeutical drugs in experimental models, such as:

  • CXCL12/stromal cell-derived factor (SDF) 1inhibitors
  • pirfenidone
  • anti-macrophage migration inhibitory factor (MIF)
  • tryptophan hydroxylase (TPH)1 inhibitor

 

Publications (Best 10 selected)

  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 
  2. 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 
  3. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension.Poble PB, Phan C, Quatremare T, Bordenave J, Thuillet R, Cumont A, Huertas A, Tu L, Dorfmüller P, Humbert M, Ghigna MR, Savale L, Guignabert C.FASEB J. 2019
  4. Ectopic Expression of the Membrane-bound IL6R Drives the Vascular Remodeling in PAH. 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 
  5. 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 
  6. Leptin signalling system as a target for pulmonary arterial hypertension therapy. Huertas A, Tu L, Thuillet R, Le Hiress M, Phan C, Ricard N, Nadaud S, Fadel E, Humbert M, Guignabert C. Eur Respir J. 2015
  7. Pro-inflammatory Signature of The Dysfunctional Endothelium In PH: Role of MIF/CD74 complex. Le Hirres M, Tu L, Ricard N, Phan C, Thuillet R, Fadel E, Dorfmuller P, Montani D, De Man F, Humbert M, Huertas A, Guignabert C.Am J Respir Crit Care Med. 2015
  8. Increased pericyte coverage mediated by endothelial-derived FGF-2 and IL-6 is a source of SMC-like cells in PH. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C.Circulation 2014
  9. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. De Man FS, Tu L, Handoko ML, Rain S, Ruiter G, François C, Schalij I, Dorfmüller P, Simonneau G, Fadel E, Perros F, Boonstra A, Postmus PE, van der Velden J, Vonk-Noordegraaf A, Humbert M, Eddahibi S, Guignabert C.Am J Respir Crit Care Med. 2012
  10. Leptin and regulatory T lymphocytes in idiopathic pulmonary arterial hypertension.Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, Fabre D, Fadel E, Eddahibi S, Cohen-Kaminsky S, Guignabert C, HumbertEur Respir J. 2012