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.