Chest
Volume 147, Issue 2, February 2015, Pages 529-537
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Translating Basic Research Into Clinical Practice
New Molecular Targets of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension: Importance of Endothelial Communication

https://doi.org/10.1378/chest.14-0862Get rights and content

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.

Section snippets

Basic Pathomechanisms Contributing to the Development and/or Progression of PAH

Pulmonary vascular lesions occurring in patients with PAH (as well as in animal models of the disease) include, to varying degrees, abnormal muscularization of distal and medial precapillary arteries, loss of precapillary arteries, thickening of the pulmonary arteriolar wall with concentric or eccentric laminar lesions, neointimal formation, fibrinoid necrosis, and the formation of complex lesions commonly named “plexiform lesions.”3 Although different forms of PAH could reflect distinct

Restoration of Functional Cellular Crosstalk Between Cells Within the Vascular Wall

Clinical and preclinical studies strongly support the idea that the aberrant local microenvironment in the pulmonary vascular wall plays a critical role in either initiation and/or perpetuation of the characteristic progressive pulmonary arterial obstruction in PAH. Investigations provide evidence that the pulmonary endothelium in PAH is a critical local source of several key mediators for vascular remodeling, including growth factors (fibroblast growth factor [FGF]-2, serotonin [5-HT],

Resolution of Inappropriate and/or Impaired Inflammatory and Immune Processes

During the last few years, greater attention has focused on the inflammatory pattern seen in plexiform lesions and other intimal lesions in PAH, and novel molecular targets are emerging.6, 24 As previously discussed, circulating levels of certain cytokines and chemokines are abnormally elevated and some have been reported to correlate with a worse clinical outcome in patients with PAH.7, 25, 26 Histopathologically, pulmonary vascular lesions occurring in patients with PAH, as well as in animal

Restoring an Appropriate Balance Between Extracellular Matrix Synthesis and Degradation

Qualitative and quantitative changes in the extracellular matrix (ECM) contribute to the aberrant local microenvironment in the remodeled pulmonary vascular wall in PAH by creating a permissive pericellular/extracellular environment for cell proliferation, survival, and migration. Inappropriate ECM remodeling can promote local pulmonary vascular remodeling in three ways: (1) the generation of fragments of ECM components known to directly modulate proliferation, migration, and protease

Homeostatic Restitution of the BMPRII/KCNK3 Signaling Systems

BMPR2 and KCNK3 are two predisposing genes for heritable PAH that encode for a type 2 receptor member (bone morphogenetic protein receptor II [BMPRII]) of the TGF-β superfamily of cell-signaling molecules and the two-pore-domain potassium channels TASK-1, respectively. Heritable PAH due to BMPR2 or KCNK3 mutations is an autosomal dominant disease with incomplete penetrance.

BMPR2 mutations are the main predisposing risk factors for heritable PAH. Mutations in this gene are identified in

Conclusions and Challenges

In summary, important discoveries in the molecular and cellular bases of pulmonary vascular remodeling associated with PAH have been reported. This knowledge continues to accelerate, thanks to key methodological approaches and tools to study PAH/PH pathogenesis, and combining findings from in situ observations, in vitro studies with primary human cells, and various relevant PH animal models. Our improved understanding of additional pathways in this condition will presumably lead to the

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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