Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major cause of morbidity and mortality. BPD is characterized by an arrest of vascular and alveolar growth and high risk for pulmonary hypertension (PH), yet mechanisms contributing to its pathogenesis and early strategies to prevent BPD are poorly understood. Strong epidemiologic studies have shown that the “new BPD” largely reflects the long-lasting impact of antenatal factors on lung development partly due to vascular dysfunction, yet data from animal models that reflect the prenatal timing of lung injury to parallel these observations are limited. Our recent prospective clinical studies have shown that antenatal determinants as assessed on the first day of life and early echocardiogram findings of PH are strongly linked with the subsequent diagnosis of BPD at 36 weeks PMA. As highlighted in recent NIH workshops, studies that define mechanisms through which antenatal stress increases the risk for BPD and PH and early strategies that accurately identify at-risk preterm infants are high research priorities. We have previously shown that disruption of vascular endothelial growth factor (VEGF) signaling impairs lung vascular growth, decreases alveolarization and causes PH in experimental BPD, and that the effects of VEGF are largely mediated through increased endothelial production of “angiocrine factors,” which mediate endothelial-epithelial interactions and are necessary for normal distal lung growth. Based on work from our prior funding period, we hypothesize that antenatal stress disrupts angiogenic signaling and impairs the production of critical angiocrine factors in the fetal lung that lead to sustained abnormalities of lung structure and PH after birth. More specifically, based on published and strong preliminary data, we seek to determine whether antenatal disruption of hypoxia- inducible factor (HIF) and insulin-like growth factor 1 (IGF-1) signaling contributes to the pathogenesis of BPD and whether enhancement of HIF and IGF-1 signaling are therapeutic strategies that would augment lung VEGF activity and have other beneficial effects for BPD prevention. We propose a series of translational studies that link in vivo models of preeclampsia and chorioamnionitis with in vitro studies using lung explants, isolated cell systems and molecular approaches to determine whether augmentation of VEGF activity and related downstream pathways through modulation of HIF or IGF-1 signaling can be targeted for developing new preventive therapies. To translate these findings to human disease, we propose to identify early changes in proteomic markers of angiogenic pathways to link antenatal stress with high risk for BPD from our clinical database. Finally, we will further apply novel imaging strategies to precisely define the impact of antenatal stress on distal lung architecture, cell-specific changes in gene expression in vivo, and endothelial-epithelial cel...