Anti-Angiogenic Preeclamptic Milieu Impairs Infant Lung and Vascular Development

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DESCRIPTION (provided by applicant): Preeclampsia, which is characterized by maternal hypertension and systemic endothelial vascular dysfunction, occurs in 3-8% of pregnancies and is associated with significant neonatal morbidities. Among infants born premature, preeclampsia is independently associated with a high risk of bronchopulmonary dysplasia (BPD), as well as an increased risk of other systemic complications. Even late preterm infants born to preeclamptic women have higher respiratory morbidity, greater rates of respiratory distress syndrome, increased rates of NICU admission, longer neonatal hospitalization, and increased respiratory support needs compared to normotensive pregnancies. The pathogenesis of preeclampsia relates to overproduction of soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which inhibits VEGF signaling. The excess sFlt-1 in maternal serum, as well as in amniotic fluid, correlates with the severity of preeclampsia. In addition, neonatal cord bloo from pregnancies complicated by preeclampsia has increased sFlt-1, reduced VEGF levels, and decreased numbers and function of angiogenic circulating progenitor cells (CPCs). Therefore, the anti-angiogenic environment of preeclampsia likely impairs angiogenic processes in the fetus and infant. We hypothesize that the anti-angiogenic environment in pregnant mothers with preeclampsia impairs pulmonary and vascular development in the infant. The overall objective of our study will be achieved in the following Specific Aims: SA #1: A) Determine whether preeclampsia impairs infant lung development, as evidenced by reduced pulmonary diffusion capacity and airway function. B) Examine whether impaired lung function is related to the angiogenic environment in cord blood, as evidenced by fewer CPCs, decreased CPC: nonCPC ratio, reduced VEGF, and increased sFlt-1. SA #2: A) Determine whether preeclampsia impairs infant systemic vascular function, as evidenced by reduced capillary density, increased vasoreactivity, and increased blood pressure. B) Examine whether impaired systemic vascular function is related to the angiogenic environment in cord blood, as evidenced by fewer CPCs, reduced CPC: nonCPC ratio, reduced VEGF, and increased sFlt-1.