In the developed world, the U.S. has the highest rate of adolescent pregnancy, which is associated with increased risk of fetal growth restriction and premature delivery. Both preterm delivery and low birth weight are associated with a much greater risk of neonatal mortality and morbidity, and, in addition, the resulting offspring may be 'programmed' to develop cardiovascular or other significant diseases later in life. While poor socio-economic status and gynecological immaturity are undoubtedly major factors predisposing adolescents to poor pregnancy outcome, maternal growth and nutritional status during pregnancy also play major roles in pregnancy outcome. The proposed studies will use well-defined animal models to examine the impacts of being overfed or underfed, and the role of altered sex steroid levels, on fetal and placental growth and placental vascular development in an ovine model of adolescent pregnancy.
Specific Aim 1 will test Hypothesis 1: that reduced fetal growth due to overnutrition of growing adolescents results from reduced placental vascular development and abnormal expression of placental angiogenic factors;
Specific Aim 2 will test Hypothesis 2: that undernutrition of growing adolescents also reduces fetal growth via altered placental growth and vascular development or, alternatively, by limiting nutrient availability in the maternal circulation;
and Specific Aim 3 will test Hypothesis 3: that reduced fetal and placental growth and vascular development in adolescents due to under- or overnutrition results from altered production or metabolism of sex steroids and, therefore, can be overcome by steroid replacement.
Specific Aim 4 will test Hypothesis 4: that placental angiogenic factor expression can be manipulated in placental tissue explants cultured in vitro using a range of specific hormone and metabolic treatments that replicate elements of those conditions observed in nutritionally compromised pregnancies in vivo. The proposed studies will provide a mechanistic understanding, at the whole animal, organ, and tissue levels, of the factors contributing to altered placental angiogenesis and angiogenic factor expression in the nutritionally compromised adolescent, and thus will provide a powerful basis for future mechanistic studies at the cellular level, while at the same time contributing to the development of informed nutritional strategies to optimize pregnancy outcome in adolescents.
