Insights into the Molecular Mechanism of Pulmonary Vein Stenosis in Pediatric Patients

BackgroundPediatric pulmonary vein stenosis (PVS) is associated with substantial morbidity and mortality for the subset of patients with recurrent or progressive disease. The molecular mechanisms underlying the development and trajectory of PVS remain unclear. This study characterizes the transcriptome of clinical and phenotypic subtypes of PVS. MethodsBulk RNA sequencing analysis was performed on human pulmonary vein tissue samples obtained from surgical interventions for pediatric patients with PVS. Transcriptomic profiles were compared for primary versus post-repair PVS as well as aggressive versus non-aggressive clinical phenotypes. Principal component analysis was performed, the differential gene expression quantified, and pathway analysis conducted based on gene ontology, KEGG and Reactome. ResultsWhen comparing AggPPVS vs NonAggPPVS, differences were noted in the genes associated in extracellular matrix regulation and PIEZO1, a mechanosensitive receptor present in endothelial cells. In addition, there were notable changes in cardiac muscle contractility, calcium handling, respiratory and energy metabolism. These results point to a potential mechanism for aggressive PPVS phenotype, due to an overexpression of PIEOZ1 in response to elevated shear stress, subsequent activation of intracellular signaling pathways and leading to reduced contractility and intracellular calcium transients with cardiomyocytes. ConclusionsThe result of this study suggests that aggressive PPVS phenotype is caused by an increase in PIEZO1 expression and subsequent changes in extracellular matrix production, heart muscle contractility and changes in calcium transients within cardiomyocytes. These results provide a potential target for therapeutic invention for primary PPVS by inhibiting the activity of PIEZO1. This could potentially reduce morbidity in this patient population.