Kelsey Holbert

Mentor: Steve Dudek

Co-mentor: Dustin R. Fraidenburg

Title: The Effects of Flow on Pulmonary Artery Endothelial Cells in the Development of Pulmonary Vascular Disease and Pulmonary Hypertension

Abstract: 

Despite significant advances in therapies, there is a more than twenty-year mortality gap in patients with sickle cell disease (SCD) and patients without SCD living in the United States. Pulmonary hypertension (PH) affects 10% of SCD patients. This diagnosis is met with significant morbidity and a median survival of just 6.8 years after diagnosis and treatment options are limited. Intravascular hemolysis is considered a major driver of PH in this population, and increased concentrations of plasma hemin correlate with both increased incidence of PH and mortality. Examining mechanisms that relate to the development and progression of pulmonary hypertension, our prior research has confirmed a direct effect of low concentrations of hemin causing pulmonary artery endothelial cell (PAEC) dysfunction and endothelial to mesenchymal transition (EndMT), through the transcription factors SNAI1/2. Another important feature of SCD that may contribute to pulmonary vascular changes and PH is the increased cardiac output and flow that blood vessels are exposed to in this disease. The anemia that results from hemolysis in SCD causes a compensatory increase in cardiac output, predominantly through a larger stroke volume, which can result in high output heart failure and pathologic flow in the pulmonary arteries. Pathologic flow is encountered in and has been implicated in the pathogenesis of not only PH, but also other vascular conditions such as systemic hypertension and atherosclerosis. We hypothesize that exposure of pulmonary artery endothelial cells to pathologic flow will reveal key transcriptomic patterns and cause endothelial dysfunction that will add to our understanding of the mechanisms of SCD-PH.