Pulmonary hypertension (PH) is a severe form of pulmonary vascular disease that results in death of up to two-thirds of affected patients within five years of diagnosis. Group 3 PH, the second deadliest category of PH, is caused by hypoxemia resulting from bronchopulmonary dysplasia (BPD), alveolar hypoventilation disorders and interstitial lung disease. Up to half of preterm infants with BPD and PH die within two years of diagnosis. In this proposal we aim to develop a mouse model for PH in preterm infants and use this model to investigate the role of endothelial cell (EC) Fibroblast Growth Factor (FGF) signaling in the pathogenesis of PH. Pathologic changes in endothelial cell function and vessel wall inflammation lead to pulmonary vascular remodeling, increased vascular resistance, decreased compliance, and gradual pulmonary vascular occlusion. Sustained increase in right heart afterload ultimately results in right heart failure. Current pharmacological treatments focused on vasodilation for symptomatic relief have limited effects on vascular remodeling. Furthermore, therapies available today were developed for Group 1 PH, and these worsen the outcome for Group 3 PH patients. A mechanistic understanding of the pulmonary vascular remodeling in Group 3 PH is thus necessary to help identify non-invasive diagnostic tools for early detection of cardiopulmonary compromise, to develop effective therapies, monitor treatment response, and improve overall outcome. In patients with PH, Fibroblast Growth Factor 2 (FGF2) and FGF Receptors 1 and 2 (FGFR1/2), are elevated in lung tissue samples. Additionally, FGF2 is elevated in a mouse model of Group 3 PH where mice are exposed to chronic hypoxia. We have implemented this physiologically relevant hypoxia mouse model mimicking Group 3 PH in our laboratory and discovered that adult mice lacking FGFR1/2 in endothelial cells develop more severe PH. Because there is an urgent unmet clinical need for prognostic biomarkers and effective therapeutics for at-risk premature infants, we have validated a stage-appropriate mouse mode for PH by demonstrating that neonatal mice develop PH when exposed to hypoxia. Here we will use neonatal hypoxia-induced PH to understand how endothelial cell FGFR1 and FGFR2 signaling modulates disease pathogenesis in vivo. We have also set up a novel in vitro microfluidic system to investigate how endothelial FGFR signaling regulates endothelial cell proliferation, permeability, and regulation of adjacent smooth muscle cells. These studies will advance our understanding of Group 3 PH pathogenesis, and establish an in vitro platform for mechanistic studies and drug discovery.
Health relevance Group 3 pulmonary hypertension affects up to 25% of preterm infants and has 50% mortality within five years of diagnosis. Current pharmacological treatments focused on vasodilation for symptomatic relief are ineffective or worsen the outcome for patients with Group 3 Pulmonary Hypertension. There is a clinical need for a mechanistic understanding of the pulmonary vascular remodeling in Group 3 Pulmonary Hypertension to help guide the development of effective therapies, to identify prognostic and pathogenic biomarkers, and to improve the overall outcome for affected patients.
