title: New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication.
abstract: Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained inflammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant inflammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more effective approaches for PAH treatment.
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors: Christophe
authors: C
authors: Guignabert
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors: Ly
authors: L
authors: Tu
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Univ. Paris-Sud, School of Medicine DHU Th orax Innovation, Kremlin-Biêtre; AP-HP Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, France.
authors: Barbara
authors: B
authors: Girerd
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors: Nicolas
authors: N
authors: Ricard
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Univ. Paris-Sud, School of Medicine DHU Th orax Innovation, Kremlin-Biêtre; AP-HP Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, France.
authors: Alice
authors: A
authors: Huertas
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Univ. Paris-Sud, School of Medicine DHU Th orax Innovation, Kremlin-Biêtre; AP-HP Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, France.
authors: David
authors: D
authors: Montani
authors: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Univ. Paris-Sud, School of Medicine DHU Th orax Innovation, Kremlin-Biêtre; AP-HP Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, France. Electronic address: marc.humbert@bct.aphp.fr.
authors: Marc
authors: M
authors: Humbert
mesh_terms: D001777:Blood Coagulation / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000503:physiopathology*; D035683:MicroRNAs / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000502:physiology; D011669:Pulmonary Wedge Pressure; D066253:Vascular Remodeling; D014664:Vasodilation / Q000502:physiology
chemical_list: D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II