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Translating Basic Research Into Clinical PracticeNew Molecular Targets of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension: Importance of Endothelial Communication
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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