Development of novel models for understanding vascular remodeling in congenital diaphragmatic hernia associated pulmonary hypertension

Abstract

Pulmonary vascular development is a highly coordinated process that underlies healthy lung function and begins as early as four weeks post-conception. This developmental program involves a combination of vasculogenesis, angiogenesis, and vascular remodeling—processes that are tightly regulated by both biochemical and mechanical cues. Disruption to this balance can result in severe structural and functional abnormalities in the pulmonary vasculature. One such condition is congenital diaphragmatic hernia (CDH), in which a defect arises during fetal development when the diaphragm fails to close properly, allowing abdominal organs to herniate into the chest cavity. This physical displacement restricts lung growth and results in two major comorbidities: pulmonary hypoplasia and pulmonary hypertension (PH). Although modern surgical and medical interventions have dramatically improved outcomes for pulmonary hypoplasia, CDH-associated pulmonary hypertension (CDH-PH) remains the leading cause of mortality in these patients. ☐ Despite its clinical significance, CDH-PH is poorly understood. Current diagnostic tools are limited in their ability to measure hemodynamic changes in utero or at the small-vessel level, where vascular remodeling is most severe. Moreover, there are no effective therapies to reverse or prevent the vascular structural changes associated with CDH-PH. To address this critical gap, new experimental and computational models are needed that can accurately capture the vascular alterations and hemodynamic consequences characteristic of this disease. ☐ This thesis presents a multifaceted modeling approach to study CDH-PH, combining computational simulations with in vivo experimentation. In Chapter 2, we introduce a novel Monte Carlo-based computational model for generating and analyzing physiologically realistic pulmonary vascular networks, enabling us to investigate how alterations in vascular structure influence blood flow and resistance. In Chapter 3, we expand upon this model to incorporate vessel growth and regression, allowing simulation of dynamic vascular remodeling processes observed during development and disease. Finally, in Chapter 4, we establish the nitrofen/bisdiamine (N/B) mouse model as a tool for studying CDH-PH. While this model has been widely used to study CDH-induced lung hypoplasia, its utility for modeling PH has not been fully validated. Through morphometric analysis of pulmonary vascular structure, we evaluate whether the N/B model recapitulates the hallmark vascular remodeling features seen in human CDH-PH. ☐ Together, these studies provide a new framework that can be used for understanding the structural and functional underlying mechanisms of CDH-associated pulmonary hypertension. By combining computational modeling with experimental validation, this work lays the foundation for future diagnostic tools and treatment strategies aimed at improving outcomes for CDH-PH patients.