ABSTRACT
In the United States, extremely preterm births account for 2% of all births and are associated with a 25% mortality
rate. These infants are at an increased risk of developing bronchopulmonary dysplasia (BPD), a devastating
disease associated with impaired alveolarization and vascular rarefication. These infants require oxygen therapy,
a life-saving treatment that causes tissue damage to their already fragile underdeveloped lungs. If an extremely
premature infant is male, the odds of developing BPD is twice that of female infants of the same age and birth
weight, suggesting there is an underlying sex-specific difference in male lungs compared to female lungs at this
gestational age. The molecular mechanisms behind this sex-based difference in developing BPD are poorly
understood. Fatty acid oxidation (FAO) is a metabolic pathway that is central to protecting vascular endothelial
cells from the damage caused by oxygen therapy as well as promoting angiogenesis. The transcription factor
peroxisome proliferator-activated receptor gamma (PPARg) upregulates FAO and is necessary for angiogenesis.
In addition, female T-cells have higher expression of PPARg compared to males, a dimorphism that can be
reversed with sex hormone estradiol supplementation in males. Our preliminary data demonstrates the same
sexual dimorphism in neonatal human pulmonary microvascular endothelial cells (HPMEC) while our estradiol
treatment contradicts this T-cell data. This contradiction highlights the importance of sex hormones and using
physiologically relevant cells, to further study signaling like PPARg. We propose that the sex-specific differences
of PPARg expression are central to the increased risk of developing BPD in males due to the role PPARg plays
in vascular endothelial cell metabolism and angiogenesis.
In both aims, we will use neonatal HPMECs to study cellular metabolism and angiogenesis. This is the ideal in
vitro model to study BPD due to the matched gestational age and tissue source of these cells to those at highest
risk for BPD: extremely premature infants. In our first Aim, we will test our proposed pathway involving PPARg
upregulation of FAO. We hypothesize that female HPMECs have higher expression of PPARg compared to
males and as such, favor FAO over glycolysis. To test our hypothesis, we will use PPARg knockdown and agonist
assays to determine the role PPARg plays in the metabolic preference of these cells. In our second Aim, we
hypothesize that sex-dependent PPARg activity governs angiogenic potential. We will use a three-dimensional
bead sprouting assay to determine this potential. In both aims, we will test the influence of sex hormones,
estradiol and dihydrotestosterone, on PPARg activity.