Alyssa B. Kalustian, Pengfei Ji, Lalita Wadhwa, Christopher A. Caldarone, Manish Bansal, Athar M. Qureshi, Jeffrey S. Heinle, Ravi K. Birla
Texas Children’s Hospital and Baylor College of Medicine.
United States
Journal of Thoracic and Cardiovascular Surgery Open
JTCVS Open 2025; 26: 166-181
DOI: 10.1016/j.xjon.2025.04.012
Abstract
Objective: Pediatric 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.
Methods: Bulk 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 postrepair PVS as well as aggressive versus nonaggressive clinical phenotypes. Principal component analysis was performed, the differential gene expression quantified, and pathway analysis conducted on the basis of Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome.
Results: When we compared aggressive (Agg) primary pulmonary vein stenosis (PPVS) versus nonaggressive (NonAgg) PPVS, 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, attributable 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 within cardiomyocytes.
Conclusions: These results suggests that aggressive PPVS phenotype may be driven by an increase in PIEZO1 expression and subsequent changes in extracellular matrix production. The clinical and therapeutic relevance of PIEZO1 warrant further investigation.
Category
Stenosis or Obstruction of Normal Pulmonary Venous Connections
Patient Factors Influencing the Onset, Severity or Outcome of Disease
Pulmonary Venous Pathology
Year of Publication: 2025
Age Focus: Pediatric
Article Type: Studies of Vascular Biology and Mechanism of Disease