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.

Public Health Relevance

Extremely premature infants are at an increased risk of developing bronchopulmonary dysplasia, a disease that is linked to defects in alveolarization and pulmonary vascular rarefication, with male infants being twice as likely to develop BPD compared to their female counterparts, an independent risk factor that is poorly understood. These studies will seek to understand how sex-specific expression of peroxisome proliferator-activated receptor gamma (PPARg) influences microvascular endothelial cell metabolism and their ability to undergo angiogenesis during lung development. As such, this work provides a mechanism behind the increased male risk and will inform treatment strategies to prevent BPD in extremely premature infants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31HL152611-01
Application #
9992466
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Natarajan, Aruna R
Project Start
2020-12-31
Project End
Budget Start
2020-12-31
Budget End
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Delaware
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716