Pulmonary arterial hypertension (PAH) is a multifactorial and life-threatening condition characterized by abnormal remodeling of distal pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and subsequent right ventricular hypertrophy and failure [1, 2]. Despite important progress in our understanding of pathways that contribute to the excessive vasoconstriction and muscularization of pulmonary vessels, current therapies fail to substantially reduce PAH progression and mortality. Thus, PAH still remains to be a significant challenge and needs to be further investigated. Recent accumulating evidence have demonstrated that epigenetic alterations, illustrated by deregulated microRNA expression, play key roles in the onset and progression of PAH [3–5]. Although, the number of miRNAs and targets involved in PAH has grown rapidly, it is nevertheless assumed that based on the complex pathogenesis of PAH (multiple triggers affecting different cell types), the current list is not exhaustive. In this issue, Gao and colleagues used an unbiased highthroughput approach coupled with bioinformatics tools to identify miRNAs and pathways implicated in end-stage idiopathic PAH [6]. The authors found that 21 miRNAs were differentially expressed in lung homogenates from PAH patients compared to controls. In order to interpret the biological impact of these miRNAs changes, they applied an in silico analysis of pathways based on the known miRNA target genes. Functional and pathway enrichment analysis revealed that the Wmt/β-catenin pathway stands among the top ranked pathways for the target genes of all the differentially expressed miRNAs. The Wnt signaling pathway is an evolutionary conserved system regulating multiple aspects of tissue development and homeostasis. The Wnt signaling has been broadly separated into two branches: the β-catenin-dependent (canonical) and the β-catenin-independent (non-canonical) pathways. The canonical Wnt signaling involves complex intracellular events culminating in cytoplasmic stabilization ofβ-catenin (through the suppression of the GSK-3β inhibition complex), which then translocates to the nucleus where it complexes with transcription factors and coactivators to initiate transcription of target genes [7]. During lung morphogenesis, the canonical Wnt signaling has been shown to be required for differentiation of vascular smooth muscle cells. Indeed, mice conditionally deleted for β-catenin in smooth muscle precursors displayed a thinner smooth muscle layer surrounding the developing blood vessels [8]. This anomaly was accompanied by a reduced expression of Tenascin C (TnC), an extracellular matrix molecule stimulating Pdgfrβ (a marker of smoothmuscle precursors) expression. In agreement with these findings, increased expression of the Wnt/TnC/Pdgfr pathway was found in human PAH [8], indicating that this signaling axis required for pulmonary vascular smooth muscle development is aberrantly overexpressed in PAH. The implication of the Wnt signaling in PAH appears not to be restricted to smooth muscle cells. Indeed, treatment of human pulmonary artery endothelial cells (HPAECs) with WNT3 (a Wnt ligand) was shown to promote proliferation, migration, and survival of HPAECs while increasing β-catenin transcriptional activity and target genes [9], suggesting that the canonical Wnt signaling may favor the proliferation of apoptosis-resistant * Olivier Boucherat olivier.boucherat@criucpq.ulaval.ca