Project Summary/Abstract: Pulmonary arterial hypertension (PAH) is a progressive vascular disorder characterized by narrowing and remodeling of the distal arterioles. Current treatment options are unable to prevent disease progression, leading to a median survival time of five years after diagnosis. Therefore, there is an urgent need to develop new disease-modifying therapies. Increased pulmonary blood flow is known to stimulate vascular remodeling in patients with congenital heart disease (CHD) and after major lung resection, although the underlying mechanism is unclear. Patients with left-to-right shunts such as ventricular septal defects and atrioventricular canal defects are at high risk for PAH. A “second hit” in the context of pulmonary overcirculation, such as hypoxia, may lead to irreversible vascular remodeling and disease progression. Current rodent models of flow-induced pulmonary hypertension (PH) such as the left pneumonectomy and SUGEN rat do not fully recapitulate patients' physiological conditions. To improve patient outcomes, animal models more representative of patients are needed, along with a better understanding of the underlying molecular mechanisms. My goal is to generate a novel animal model to study flow-induced PH. Establishing a murine model of PH that mimics patients with CHD will enable the development of therapeutics capable of reversing flow-induced vascular remodeling. The second goal of this proposal is to discover key insights into the response of smooth muscle cells (SMCs) to vascular remodeling from increased pulmonary blood flow. Specifically, the aims of this proposal are to 1. Develop a new mouse model of flow-induced PH that better represents patients' physiological conditions, 2. Describe the contribution and underlying mechanisms in which SMCs contribute to shear stress- induced vascular remodeling, and 3. Discover novel therapeutic approaches for patients with PAH-CHD.