UC San Diego

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an elevated mean pulmonary arterial pressure leading to right ventricular hypertrophy and failure. PAH is also associated with an increase in pulmonary vasculature resistance (PVR) due to the accumulation and proliferation of smooth muscle and endothelial cells in the intimal layer of the distal pulmonary arteries. This causes remodeling of the pulmonary vasculature, similar to the plexiform like lesions seen on the autopsy of PAH patients. Many studies have investigated the microstructural and mechanobiological properties of the pulmonary arteries however, the main cause initiating this remodeling process still remains unknown. In this thesis, the remodeling of pulmonary arteries that causes the changes in the resistance and compliance properties of pulmonary vasculature as PAH progresses overtime was studied, using three different Sugen Hypoxia treated rat models (male, female, ovariectomized female) of PAH. A lumped three-element Windkessel model was used to reproduce the in vivo measured blood pressure data efficiently by estimating the resistance and compliance parameters. The parameters estimated by the three-element Windkessel model exhibited statistically significant differences and reflected the relevant physiological changes as the disease progressed. For example, our model revealed that the resistance and compliance changes during PAH, and that the resistance significantly increases (p < 0.05) only in male however the compliance significantly decreases (p < 0.05) in all three groups of rats. Also, the remodeling was sex specific because the compliance changes significantly and early in all three groups of rats before any major changes in the resistances for female and ovariectomized females (OVX) were observed. On the other hand, no statistically significant differences in the parameters and pressures were found between the female and OVX rats. Future direction for this study includes the development of one-dimensional fluid dynamic model to better understand the sex specific remodeling and compare these changes to the structural and tissue-level changes of biomechanical properties in the pulmonary arteries of male, female and OVX female rats. Such insights can potentially help improve our understanding of treatment therapies in either sex of PAH patients in future.