Sex-Selective Increase of IGF-2 Expression in the Hypoxic Guinea Pig Placenta of Growth-Restricted Fetuses.

Abstract

Chronic hypoxia can cause fetal growth restriction (FGR) through placental dysfunction. Insulin-like growth factors (IGFs), such as IGF-2, play a major role in preservation of placental growth and function. We investigated the effects of chronic hypoxia and sex on protein expression of the IGF-2 pathway in placentas selected from asymmetric-FGR fetuses. Time-mated pregnant guinea pigs were assigned to normoxia (NMX, 21% O2) or hypoxia (HPX, 10.5% O2) during the last 14days of pregnancy. Placentas were selected from male and female symmetrically grown NMX fetuses (fetal wt between 25th ile-75th ile) and HPX fetuses of asymmetric-FGR (fetal wt < 25th ile and brain:liver wt > 50th ile). Effects of HPX and sex on placenta protein expression of the IGF-2 signaling proteins (IGF-2, PI3K, AKT-P, total AKT, PCNA, a cell proliferation marker) were evaluated by immunoblotting. Effects of HPX and sex on morphometric parameters were analyzed using two-way ANOVA (p < 0.05). HPX reduced (p < 0.005) fetal wt by ~ 35% compared to NMX in both sexes. Expression of IGF-2 was lower (p = 0.029) in NMX female placentas compared to males. Despite lower NMX levels, HPX increased (p < 0.05) expression of IGF-2, AKT-P, relative AKT-P, and PCNA in female placentas only and had no effect on protein expression in male placentas. The female guinea pig placenta exhibits a greater sensitivity than males to HPX in upregulating expression of the IGF-2 axis. In addition, the sex difference in baseline IGF-2 expression suggests a greater capacity for females to increase IGF-2 in response to HPX as a placental adaptation in FGR.