Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth

Abstract

The placenta is the main determinant of fetal growth and development in utero. It supplies all the nutrients and oxygen required for fetal growth and secretes hormones that facilitate maternal allocation of nutrients to the fetus. Furthermore, the placenta responds to nutritional and metabolic signals in the mother by altering its structural and functional phenotype, which can lead to changes in maternal resource allocation to the fetus. The molecular mechanisms by which the placenta senses and responds to environmental cues are poorly understood. This review discusses the role of the insulin-like growth factors (IGFs) in controlling placental resource allocation to fetal growth, particularly in response to adverse gestational environments. In particular, it assesses the impact of the IGFs and their signalling machinery on placental morphogenesis, substrate transport and hormone secretion, primarily in the laboratory species, although it draws on data from human and other species where relevant. It also considers the role of the IGFs as environmental signals in linking resource availability to fetal growth through changes in the morphological and functional phenotype of the placenta. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing adult-onset diseases in later life, understanding the role of IGFs during pregnancy in regulating placental resource allocation to fetal growth is important for identifying the mechanisms underlying the developmental programming of offspring phenotype by suboptimal intrauterine growth.

Keywords: IGF; fetus; nutrient transport; placenta; pregnancy; resource allocation; signalling.

Figure 1. Impact of exogenous IGFs on the placenta

A, the effect of exogenous IGFs on placental human trophoblast in vitro. Proposed signalling pathways mediating the actions of IGFs are shown. B, the effect of exogenous maternal IGFs on the mouse, rat and/or guinea pig placenta in vivo. Dashed lines indicate a potential interaction (A) or impact (B) of IGF1. IGF, insulin‐like growth factor; IGF1R, type 1 IGF receptor; IGF2R, type 2 IGF receptor; INSR, insulin receptor; Jz, junctional zone; Lz, labyrinthine zone; MAPK, mitogen‐activated protein kinase; PI3K, phosphoinositol 3‐kinase.

Figure 2. The effect of genetically manipulating IGF2 expression or signalling on placental phenotype in mice

A and B, the effect of complete loss of IGF2 (A) and the effect of partial loss of IGF2 (B), either by deleting the placental‐exclusive isoform, Igf2P0 or through a constitutive heterozygous deficiency of PI3K‐p110α. Dashed line indicates a potential interaction of IGF2 with receptor. Line with a round head indicates parameters reduced by loss of IGF2 signalling. Loss of IGF2 signalling leads to reductions in placental development and transport function (A). Partial loss of IGF2 signalling also leads to reductions in placental development, but is associated with adaptive up‐regulation in transport function (B). AA, amino acids; IGF, insulin‐like growth factor; IGF1R, type 1 IGF receptor; Lz, labyrinthine zone; GLUT, glucose transporter; MAPK, mitogen‐activated protein kinase; PI3K, phosphoinositol 3‐kinase; SNAT, sodium‐coupled amino acid transporter; XRp, unknown placental‐specific IGF receptor.

Figure 3. The effect of different environmental manipulations on the placental IGF system and resource allocation phenotype in the mouse

A, manipulations that down‐regulate IGF2 signalling. B, manipulations that up‐regulate IGF2 signalling. AKT, protein kinase B; IGF, insulin‐like growth factor; Lz, labyrinthine zone. ^*Note Igf2P0 is required for the placenta to up‐regulate amino acid transport to the fetus in response to maternal undernutrition.