Dear Colleagues,

Pulmonary arterial hypertension (PAH) is a serious cardiopulmonary–vascular condition with no readily available cure. It is characterized by progressive angioproliferative remodeling of the precapillary vessel, resulting in vasoconstriction and a significant increase in pulmonary vascular resistance, which ultimately leads to right ventricle failure and premature death. The obliterative remodeling is sustained by dysfunctions of the lung vessel cells that release mitogens and vasoconstrictors with an imbalance of cell proliferation versus cell death. The etiology of PAH is complex and may be mediated by the interplay of a predisposed genetic background, epigenetic state and injurious events. Most of the genetic mutations associated with PAH have been identified in genes of the TGF beta superfamily that code for receptors involved in the regulation of cell proliferation and endothelial to mesenchimal transition; the most characterized and representative gene in this family is the Bone Morphogenetic Protein Receptor 2 (BMPR2). Other genes identified as involved in proliferative vasoconstrictive signaling pathways are Caveolin 1, Endoglin, Translation Initiation Factor 2 Alpha Kinase 4, Kruppel Like Factor 2, Potassium Two Pore Domain Channel Subfamily K Member 3 and others. On the epigenetic side, alterations in the DNA methylation state at key gene loci, as well as modifications of the histone H1 and histone deacetylase levels, have been shown to play important roles in the hyperproliferative and veno-occlusive processes. Moreover, dysregulation of microRNA networks or mutations in microRNA-targeted sequences represent other important epigenetic players in the pathogenesis of PAH. Epigenetic mechanisms might explain the great variability in susceptibility to environmental cues in PAH progression and severity and might be relevant to the female predisposition to PAH and the incomplete penetrance of BMPR2 mutations in familial PAH. Overall, these observations clearly indicate that a global perspective of the molecular network underlying the PAH phenotype is necessary to design novel therapeutic strategies.

This Special Issue of IJMS, “Pulmonary arterial hypertension: from genetics to epigenetics”, will cover a selection of recent research topics related to advances in the comprehension of the genetic and epigenetic mechanisms involved in the establishment of PAH. Up-to-date review articles, commentaries and experimental papers are all welcome.

Dr. Letizia Pitto
Dr. Giuseppina Nicolini
Guest Editors

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