Project 172201

The placenta is a critically important organ for successful pregnancy. In the placenta, maternal blood rich in oxygen and nutrients bathes the fetal villi. They absorb these substances and they are transported to the fetus in the umbilical cord to support fetal growth. The villi are packed full of fetal blood vessels in a healthy placenta, but blood vessels may be sparce in fetuses whose growth is abnormally slow during pregnancy. Similarly, the flow of blood from the maternal side is often low in women with preeclampsia, a life-threatening disorder in the mother. In women with small fetuses or who have preeclampsia the normal increase in sflt1, a factor that inhibits blood vessel growth, is accelerated. Evidence suggests high sflt1 inhibits blood vessel growth and can cause these diseases. Treatments to block the rise in sflt1 are contemplated, yet the normal function of the late-pregnancy rise is unknown. The current proposal investigates the normal role for sflt1 in placental blood vessel density and maternal function in mutant mice. Since evidence suggests sflt1 is produced by the fetal trophoblast cells that form the placenta, we will use mutant mice to specifically delete sflt1 in these cells. We anticipate that this will blunt the normal increase in sflt1 in late gestation in the mother. We will then examine the effect of this intervention on the placenta and the mother. sflt1 is believed to act by reducing levels of the blood vessel growth factor, VEGF. So, we will see if inhibiting VEGF production by trophoblast cells using other types of mutant mice reduces placental vessel density and/or causes preeclamptic changes in the mother. These studies will help us understand the role of sflt1 and VEGF in normal pregnancy leading to a better understanding of how abnormal levels of these substances cause disease in pregnancy.