Cailin R. Gonyea, Yuanjun Shen, Katherine M. Nelson, Rylie N. Bird, Rachel M. Gilbert, Oluyinka O. Olutoye II, Sundeep G. Keswani, Jason P. Gleghorn
University of Delaware. Baylor College of Medicine.
United States
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2025;
DOI: 10.1152/ajplung.00233.2024
Abstract
CDH-associated pulmonary hypertension (CDH-PH) has severe implications for the survival of CDH patients; however, CDH-PH is often refractory to pulmonary vasodilators, rendering it difficult to treat. As such, models are necessary to study the etiology, mechanism, onset, and progression of pulmonary vascular remodeling in CDH. Despite several established murine models of CDH, no characterized CDH-PH or CDH-associated pulmonary vascular remodeling murine model exists. In this work, we assessed the nitrofen/bisdiamine (N/B) murine CDH model for PH hallmarks, to establish its usefulness as a model for studying mechanisms leading to CDH-PH. To do so, we evaluated key metrics of vascular PH at two different gestational time points and compared the results to sex and age-matched human CDH tissue sections and results from a meta-analysis of published data of human CDH samples. We found that vessel rarefaction, smooth muscle hypertrophy, and adventitial ECM deposition were present in the N/B CDH murine model at E18.5 in late gestation. Additionally, this same vascular PH phenotype was present much earlier in development at E16.5, after normal diaphragmatic development and closure, but still within the pseudoglandular phase of lung development. Lastly, comparisons to human CDH data confirm that the N/B CDH murine model recapitulates the pulmonary hypertension vascular phenotype seen in human CDH lung sections. Together these data validate a mouse CDH-PH model with the ability to genetically perturb pathways that may exacerbate or improve CDH-PH outcomes, which could, in turn, lead to therapies or diagnostic markers of CDH-PH severity in utero.
Category
Class III. Pulmonary Hypertension Associated with Lung Hypoplasia
Animal Models of Pulmonary Vascular Disease and Therapy
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes