Amanda N. Sferruzzi-Perri

Placental efficiency and adaptation: endocrine regulation

Size at birth is critical in determining life expectancy and is dependent primarily on the placental supply of nutrients. However, the fetus is not just a passive recipient of nutrients from the placenta. It exerts a significant acquisitive drive for nutrients, which acts through morphological and functional adaptations in the placenta, particularly when the genetically determined drive for fetal growth is compromised by adverse intrauterine conditions. These adaptations alter the efficiency with which the placenta supports fetal growth, which results in optimal growth for prevailing conditions in utero. This review examines placental efficiency as a means of altering fetal growth, the morphological and functional adaptations that influence placental efficiency and the endocrine regulation of these processes.

Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy

In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.

An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory

In developed societies, high‐sugar and high‐fat (HSHF) diets are now the norm and are increasing the rates of maternal obesity during pregnancy. In pregnant rodents, these diets lead to cardiovascular and metabolic dysfunction in their adult offspring, but the intrauterine mechanisms involved remain unknown. This study shows that, relative to standard chow, HSHF feeding throughout mouse pregnancy increases maternal adiposity (+30%, P<0.05) and reduces fetoplacental growth at d 16 (–10%, P<0.001). At d 19, however, HSHF diet group pup weight had normalized, despite the HSHF diet group placenta remaining small and morphologically compromised. This altered fetal growth trajectory was associated with enhanced placental glucose and amino acid transfer (+35%, P<0.001) and expression of their transporters (+40%, P<0.024). HSHF feeding also up‐regulated placental expression of fatty acid transporter protein, metabolic signaling pathways (phosphoinositol 3‐kinase and mitogen‐activated protein kinase), and several growth regulatory imprinted genes (Igf2, Dlk1, Snrpn, Grb10, and H19) independently of changes in DNA methylation. Obesogenic diets during pregnancy, therefore, alter maternal nutrient partitioning, partly through changes in the placental phenotype, which helps to meet fetal nutrient demands for growth near term. However, by altering provision of specific nutrients, dietary‐induced placental adaptations have important roles in programming development with health implications for the offspring in later life.—Sferruzzi‐Perri, A N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson‐Smith, A C., Burton, G. J., Con‐stancia, M., Fowden, A. L., An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB J. 27, 3928–3937 (2013). www.fasebj.org

Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice.

The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother.

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth

Maternal insulin‐like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming.

Distinct Actions of Insulin-Like Growth Factors (IGFs) on Placental Development and Fetal Growth: Lessons from Mice and Guinea Pigs

Placental insufficiency is thought to be a key factor in many cases of intrauterine growth restriction which complicates about 6% of pregnancies in western countries. Understanding the molecular control of placental and fetal growth is essential to identifying diagnostic and therapeutic targets to improve pregnancy success. Insulin-like growth factor (IGF)-I and IGF-II gene ablation or maternal food restriction reduce tissue and circulating IGF abundance in the fetus, placenta and mother and are associated with both placental and fetal growth restriction. Conversely, in vivo treatment of the pregnant guinea pig with IGF-I or IGF-II from early to mid pregnancy increases fetal weight and enhances placental transport near term. IGF-II, and an IGF2R specific analogue, enhanced placental structural differentiation, whereas IGF-I altered maternal body composition. These outcomes demonstrate endocrine roles within the mother for both IGFs, as well as autocrine/paracrine effects of IGF-II in enhancing placentation and pregnancy success. Therefore, factors that alter placental expression of IGF-II, or maternal circulating IGF-I or IGF-II in early pregnancy may affect placental exchange function late in gestation when the demands of the fetus escalate. IGF-II within the fetus may also signal its nutrient demands to the placenta to improve its function to suit. Therefore each IGF of endocrine and local origin has important, but distinct, roles in placental development and function.

Maternal corticosterone regulates nutrient allocation to fetal growth in mice

•  Stress during pregnancy leads to fetal growth restriction. •  Natural glucocorticoids, such as corticosterone, are elevated by maternal stress and, hence, may mediate the effects of stress on fetal growth. •  This study shows that increasing corticosterone levels in pregnant mice limits fetal growth by reducing the amino acid supply and density of blood vessels in the placenta. •  The findings suggest that excess corticosterone may act to defend maternal resources during times of stress by constraining the placental allocation of nutrients to the fetus. •  The results also provide a potential mechanism by which stresses during pregnancy can program intrauterine growth and development with consequences in later life.

The Programming Power of the Placenta

Size at birth is a critical determinant of life expectancy, and is dependent primarily on the placental supply of nutrients. However, the placenta is not just a passive organ for the materno-fetal transfer of nutrients and oxygen. Studies show that the placenta can adapt morphologically and functionally to optimize substrate supply, and thus fetal growth, under adverse intrauterine conditions. These adaptations help meet the fetal drive for growth, and their effectiveness will determine the amount and relative proportions of specific metabolic substrates supplied to the fetus at different stages of development. This flow of nutrients will ultimately program physiological systems at the gene, cell, tissue, organ, and system levels, and inadequacies can cause permanent structural and functional changes that lead to overt disease, particularly with increasing age. This review examines the environmental regulation of the placental phenotype with particular emphasis on the impact of maternal nutritional challenges and oxygen scarcity in mice, rats and guinea pigs. It also focuses on the effects of such conditions on fetal growth and the developmental programming of disease postnatally. A challenge for future research is to link placental structure and function with clinical phenotypes in the offspring.

Environmental regulation of placental phenotype: implications for fetal growth

Environmental conditions during pregnancy determine birthweight, neonatal viability and adult phenotype in human and other animals. In part, these effects may be mediated by the placenta, the principal source of nutrients for fetal development. However, little is known about the environmental regulation of placental phenotype. Generally, placental weight is reduced during suboptimal conditions like maternal malnutrition or hypoxaemia but compensatory adaptations can occur in placental nutrient transport capacity to help maintain fetal growth. In vivo studies show that transplacental glucose and amino acid transfer adapt to the prevailing conditions induced by manipulating maternal calorie intake, dietary composition and hormone exposure. These adaptations are due to changes in placental morphology, metabolism and/or abundance of specific nutrient transporters. This review examines environmental programming of placental phenotype with particular emphasis on placental nutrient transport capacity and its implications for fetal growth, mainly in rodents. It also considers the systemic, cellular and molecular mechanisms involved in signalling environmental cues to the placenta. Ultimately, the ability of the placenta to balance the competing interests of mother and fetus in resource allocation may determine not only the success of pregnancy in producing viable neonates but also the long-term health of the offspring.

Hormonal and nutritional drivers of intrauterine growth.

Purpose of review Size at birth is critical in determining life expectancy with both small and large neonates at risk of shortened life spans. This review examines the hormonal and nutritional drivers of intrauterine growth with emphasis on the role of foetal hormones as nutritional signals in utero. Recent findings Nutrients drive intrauterine growth by providing substrate for tissue accretion, whereas hormones regulate nutrient distribution between foetal oxidative metabolism and mass accumulation. The main hormonal drivers of intrauterine growth are insulin, insulin-like growth factors and thyroid hormones. Together with leptin and cortisol, these hormones control cellular nutrient uptake and the balance between accretion and differentiation in regulating tissue growth. They also act indirectly via the placenta to alter the materno-foetal supply of nutrients and oxygen. By responding to nutrient and oxygen availability, foetal hormones optimize the survival and growth of the foetus with respect to its genetic potential, particularly during adverse conditions. However, changes in the intrauterine growth of individual tissues may alter their function permanently. Summary In both normal and compromised pregnancies, intrauterine growth is determined by multiple hormonal and nutritional drivers which interact to produce a specific pattern of intrauterine development with potential lifelong consequences for health.