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New Molecular Targets of Pulmonary Vascular Remodeling in Pulmonary Arterial HypertensionPulmonary Arterial Hypertension Molecular Targets: Importance of Endothelial Communication

Christophe Guignabert, PhD; Ly Tu, PhD; Barbara Girerd, PhD; Nicolas Ricard, PhD; Alice Huertas, MD, PhD; David Montani, MD, PhD; Marc Humbert, MD, PhD
Author and Funding Information

From INSERM UMR_S 999 (Drs Guignabert, Tu, Girerd, Ricard, Huertas, Montani, and Humbert), LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Univ. Paris-Sud, School of Medicine (Drs Guignabert, Tu, Girerd, Ricard, Huertas, Montani, and Humbert), DHU Thorax Innovation, Kremlin-Bicêtre; and AP-HP (Drs Girerd, Huertas, Montani, and Humbert), Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, France.

CORRESPONDENCE TO: Marc Humbert, MD, PhD, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Service de Pneumologie, 78 rue du Général-Leclerc, 94275 Le Kremlin Bicêtre cedex, France; e-mail: marc.humbert@bct.aphp.fr


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(2):529-537. doi:10.1378/chest.14-0862
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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.

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