Hypertension Artérielle Pulmonaire (HTAP) : Vers une nouvelle voie pour lutter contre le remodelage vasculaire pulmonaire

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1 Hypertension Artérielle Pulmonaire (HTAP) : Vers une nouvelle voie pour lutter contre le remodelage vasculaire pulmonaire Christophe GUIGNABERT CR1 INSERM Research group: Cellular and molecular bases of pulmonary endothelial dysfunction in PAH INSERM UMR_S 999 Univ. Paris Sud Université Paris-Saclay Pulmonary Hypertension: Physiopathology and Novel Therapies Directeur : Pr Marc Humbert

2 La Circulation Pulmonaire : spécificités structurelles et fonctionnelles ① The pulmonary circulation is a high flow, low-resistance, low-pressure system þ a high compliance of pulmonary pre-capillary arterioles characterized by a thin media Pulmonary endothelium þ a high capacity to recruit vessels available ü The Vasoconstrictors (i.e. ET-1, AngII) ② pulmonary artery carries5-ht, oxygen-poor from the right ventricle ü blood Vasodilators (i.e. NO, PGI2) of the heart to the lungs ü Activators and inhibitors of SMC growth and hypoxic migrationstimulus induces ③ The of the pulmonary ü vasoconstriction Pro- and anti-thrombotic mediatorsarteries, more pronounced as signals the vessel ü effect Pro- and anti-inflammatory diameter decreases Remodelage vasculaire pumonaire mean pulmonary arterial pressure = 14 +/- 3 mmhg mean arterial pressure = 100 mmhg

3 Classification Clinique de l Hypertension Pulmonaire : Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure 25 mmhg at rest, measured during right heart catheterization. 2 Ø Consequences: Right ventricular hypertrophy Right heart failure Dyspnea, disability, syncope, death 1 PAH Pulmonary artery wedge pressure (PAWP) 15 mmhg PVOD or/and PCH 5 1 Galiè N et al Eur Respir J Simonneau G et al J Am Coll Cardiol

4 Remodelage vasculaire pulmonaire associé à l Hypertension Artérielle Pulmonaire (HTAP) Lymphoid follicles in remodeled arteries Hypertrophy/ hyperplasia of the media Concentric intimal fibrosis Plexiform lesions PAH Pulmonary arteries Guignabert C. and Dorfmüller P, Semin Respir Crit Care Med, 2013.

5 Composantes du remodelage vasculaire pulmonaire associé à l Hypertension Artérielle Pulmonaire (HTAP) Guignabert C, Tu L, Girerd B, Ricard N, Huertas A, Montani D, Humbert M. Chest 2015.

6 Groupe Bases cellulaires et moléculaires de la dysfonction endothéliale pulmonaire HTAP Role of MIF/CD74 complex Role of pulmonary PERICYTES Role of Genetic & Environmental Factors Abnormal Endothelial Cell Phenotype Hyper-proliferation & Apoptosis resistance Pro-inflammatory phenotype FGF2 / EGF / PDGF IL-6 / Leptin P130 cas / Src TPH / Serotonin ACE / Ang-II BCL2 / BCL-xL MAPK Inflammation Immune cell recruitment Smooth Muscle Cell Hyperplasia Vasoconstriction Hypercoagulability

7 1 ANR JCJC EPINE : Rôle de la voie MIF/CD74 dans l HTAP à l interface entre Inflammation et Dysfonction endothéliale Inflammation & Immune cell recruitment Imbalance between Vasodilation Vasoconstriction MIF/CD74 Pathway Endothelial Cell Proliferation & Apoptosis resistance phenotype Thèse de Morane LE HIRESS Bourse LERMIT ANR-12-JSV

8 1 ANR JCJC EPINE : Rôle de la voie MIF/CD74 dans l HTAP à l interface entre Inflammation et Dysfonction endothéliale In vitro: Serum MIF protein level: Control In situ: CTR idiopathic PAH ipah CD74 CD74 β-actin MIF% Endothelial+ cells+ CD74% Src%Kinase% PI3K/Akt% MAPK/ERK% NFκB% ProliferaDon! Cell%Cycle% InflammaDon% Cell%survival% Apoptosis% Cytokines% Proliferation Inflammation Cell survival Cell Cycle Cytokines Apoptosis release Le Hiress M et al., Am J Respir Crit Care Med, 2015.

9 1 ANR JCJC EPINE : Rôle de la voie MIF/CD74 dans l HTAP à l interface entre Inflammation et Dysfonction endothéliale MIF-antagonist, ISO-1 (30 mg.kg -1.day -1 ) monocrotaline injection daily i.p. administration ISO-1 TREATMENT weeks Vehicle MCT MCT + ISO-1 mpap RVH Pulmonary Arterial Muscularization *** ** *** ** Vehicle MCT MCT + ISO-1 H&E mm Hg 20 RV/(LV+S) α-sma n=7 n=7 n=7 n=7 n=7 n=7 0.0 Le Hiress M et al., Am J Respir Crit Care Med, 2015.

10 1 ANR JCJC EPINE : Rôle de la voie MIF/CD74 dans l HTAP à l interface entre Inflammation et Dysfonction endothéliale MIF Immune cell recruitment & adherence Cytokine / Chemokine secretion ISO-1 Adhesion molecules CD74 Dysfunctional pulmonary endothelium in PAH Le Hiress M et al., Am J Respir Crit Care Med, 2015.

11 Vers le développement de nouveaux antagonistes de MIF 1 ANR EPINE : Endothelial-CD74 in PAH at the crossroad of Inflammation and Endothelial dysfunction Imbalance between Vasodilation Vasoconstriction To evaluate new small molecule inhibitors of MIF and their ability to reduce the severity of experimental of PH: Inflammation & Immune cell recruitment MIF/CD74 Pathway Endothelial Cell Proliferation & Apoptosis resistance phenotype Dr. Gaël Jalce CEO & Founder, Paris, France Le Hiress M et al., Am J Respir Crit Care Med, Patents: EP A1 - WO 2015/ A1.

12 Groupe Cellular and Molecular Bases of Pulmonary Endothelial Dysfunction in PAH Role of MIF/CD74 complex Role of pulmonary PERICYTES Role of Genetic & Environmental Factors Abnormal Endothelial Cell Phenotype Hyper-proliferation & Apoptosis resistance Pro-inflammatory phenotype FGF2 / EGF / PDGF IL-6 / Leptin P130 cas / Src TPH / Serotonin ACE / Ang-II BCL2 / BCL-xL MAPK Inflammation Immune cell recruitment Dr. Alice HUERTAS (Concours CR INSERM) Smooth Muscle Cell Hyperplasia Vasoconstriction Hypercoagulability

13 2 Rôle des péricytes pulmonaires dans l Hypertension Artérielle Pulmonaire (HTAP) Vessel stabilization Immune regulation Pericytes Mesenchymal potential Isolectin NG2 Vascular tone ECM remodeling

14 2 Rôle des péricytes pulmonaires dans l Hypertension Artérielle Pulmonaire (HTAP) Human lungs: 3G5 α-sma DAPI 20 Control Pericyte number /vessel ** 16 PAH 12 *** Control 8 *** 3G5 α-sma DAPI 4 0 < 100 µm µm > 200 µm Pericyte number/vessel is increased by 2-fold in PAH lung specimens as compared to controls. ipah Ricard N et al. Circulation, 2014.

15 2 Rôle des péricytes pulmonaires dans l Hypertension Artérielle Pulmonaire (HTAP) Increased pericyte coverage FGF-2 IL-6 Differentiation into smooth muscle-like cells TGF-β Equipe FRM 2015 Thèse de Jennifer Bordenave (Bourse en Pneumologie - FRM) Ricard N et al. Circulation, 2014.

16 Groupe Bases cellulaires et moléculaires de la dysfonction endothéliale pulmonaire HTAP Role of MIF/CD74 complex Role of pulmonary PERICYTES Role of Genetic & Environmental Factors Abnormal Endothelial Cell Phenotype Hyper-proliferation & Apoptosis resistance Pro-inflammatory phenotype FGF2 / EGF / PDGF IL-6 / Leptin P130 cas / Src TPH / Serotonin ACE / Ang-II BCL2 / BCL-xL MAPK Inflammation Immune cell recruitment Smooth Muscle Cell Hyperplasia Vasoconstriction Hypercoagulability

17 3 Rôle des Facteurs Génétiques et Environnementaux pour le remodelage vasculaire pulmonaire HTAP :?? Thèse du Dr. Maria-Rosa GHIGNA Pathologiste Bone Morphogenetic Protein Receptor type 2 (BMPR2) gene mutations affect the structure and function of the pulmonary arterial bed INSERM UMR_S 1018 Recherche biostatistique Analyse de signaux Thèse du Carole PHAN «VIGIAPATH» CNR HTAP Recherche clinique Auto-questionnaire +/- bilan d exposition médicamenteuse INSERM UMR_S 999 Compréhension des mécanismes physiopathologiques

18 3 Rôle des Facteurs Génétiques et Environnementaux pour le remodelage vasculaire pulmonaire HTAP : Vehicle Dasatinib 1 mg/kg Dasatinib 10 mg/kg Imatinib 20 mg/kg mpap (mm Hg) Fulton Index (%) Phan C et al. (soumis)

19 Remerciements INSERM UMR_S 999 Merci pour votre Attention! Equipe «Dysfonction Endothéliale» «Hypertension Pulmonaire» Physiopathologie et Innovation Thérapeutique Pr. Marc Humbert Pr. Gérald Simonneau Pr. Philippe Dartevelle Pr. Elie Fadel Pr. Olivier Sitbon Pr. Peter Dorfmüller Pr. Olaf Mercier Dr. David Montani Dr. Sylvia Cohen-Kaminsky Dr. Frédéric Perros Dr. Andrei Seferian Dr. Caroline Sattler Alice Huertas (MD, Post-Doc) Yuichi Tamura (MD, Post-doc) Nicolas Ricard (Post-Doc) Morane Le Hiress (Post-doc) Ly Tu (Research Engineer) Raphaël Thuillet (Engineer) Maria-Rosa Ghigna (MD, Ph.D) Carole Phan (Ph.D) Jennifer Bordenave (Ph.D)