Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY / ABSTRACT People born preterm are at risk for developing pulmonary hypertension (PH) and heart failure that will profoundly shorten their lifespan. This is an emerging epidemic of growing concern because conservative estimates suggest there are 4 million survivors of preterm birth living in the United States, 40% of which have subclinical PH. The risk of developing disease is highest in adults born extremely preterm and thus directly associated with their need for supplemental oxygen (hyperoxia) at birth. But how hyperoxia at birth triggers disease, and whether PH and heart failure are integrated or separate diseases is not known. We propose to fill this gap in knowledge using lungs of preterm infants, adults who were born preterm, and an established mouse model wherein hyperoxia between postnatal days (PND) 0-4 causes PH via three distinct stages. The first or priming stage occurs when the lung is exposed to hyperoxia. During this time, hyperoxia stimulates endothelial expression of angiotensin converting enzyme (ACE) responsible for producing the vasoconstrictive peptide angiotensin (Ang) II and driving PH when uncontrolled. Hyperoxia also suppresses proliferation of cardiomyocytes lining the pulmonary vein and extending into the left atrium, resulting in left atrial dilation and insufficient filling of the left ventricle. This is followed by a latency period where ACE and Ang II levels continue to increase even though the lung is no longer in hyperoxia and the loss of atrial cardiomyocytes causes progressive diastolic dysfunction. The third or disease stage is characterized by high NADPH oxidase (NOX) 3 in pericytes, vascular remodeling and congestion, and mortality. The high expression of NOX3 in pericytes was unexpected and may explain why hyperoxia causes post-capillary remodeling, thus distinguishing it from pulmonary arterial hypertension (PAH) where smooth muscle cells express NOX4. Building off these findings, we hypothesize neonatal hyperoxia stimulates expression of ACE in pulmonary endothelial cells, which persists and increases because of ongoing endothelial injury and diastolic dysfunction, and causes PH when it dysregulates Ang II and NOX3 later in life. We will determine how hyperoxia regulates ACE in pulmonary endothelial cells (Aim 1), how NOX3 contributes to vascular remodeling (Aim 2), and whether suppressing ACE/Ang II signaling effectively reduces PH and diastolic dysfunction caused by hyperoxia (Aim 3). Understanding how hyperoxia causes cardiovascular disease could advance new concepts on how to best manage it in people born preterm.
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