The pivotal role of insulin-like growth factors in pregnancy success.

Appropriate placental development in early gestation is essential for subsequent placental function and hence optimal fetal growth and pregnancy outcome. Placental insufficiency has been implicated in common disorders of pregnancy, which result in fetal and maternal mortality or morbidity, and also increase the risk of poor health in adult offspring. Prior to the onset of maternal blood flow to the placenta at ~10 weeks of gestation, placentation occurs in a relatively hypoxic environment, which is essential for healthy pregnancy. IGF-II is abundantly expressed by the invasive trophoblast and may interact with oxygen to regulate placentation. Additionally, maternally-derived IGFs may act on the placenta and the mother to regulate fetal growth. This thesis investigated the role and interaction of oxygen and IGF-II on human placental outgrowth during early pregnancy in vitro. Furthermore, the impact of maternal IGF treatment during early to mid pregnancy, on placental development and substrate transfer, nutrient partitioning between the mother and fetus, and fetal growth, were also determined in mid and late gestation in guinea pigs. We have demonstrated, using human early first trimester placental villous explants, that IGF-II mediates the effect of hypoxia on placental outgrowth. Culture of placental explants in hypoxia, or with exogenous IGF-II, enhanced trophoblast outgrowth and inhibited TGF-β1 activation, a negative regulator of trophoblast function. In addition, culture of explants in hypoxia induced Igf2 gene expression in outgrowing trophoblast, without altering Upar, Igf1r, Igf2r or Tgfβ1 transcription. We propose that this novel interaction of oxygen, IGF-II and TGF-β1 during pregnancy is an important determinant of placental development. Furthermore, we showed that exogenous IGF-II stimulates villous explant trophoblast outgrowth in placenta from >10 weeks gestation, suggesting that IGF-II may be a potential therapeutic agent to enhance placental growth. In guinea pigs, maternal treatment with IGF-I or IGF-II, in early to mid pregnancy, has sustained anabolic effects on fetal growth, enhanced fetal survival and increased placental delivery, and fetal and maternal utilization of, glucose and amino acids near term. These effects were also evident by mid gestation following earlier IGF-I treatment. Despite these similar pregnancy outcomes, there were IGF specific effects on the placenta and mother, suggesting that IGFs may mediate some of their effects via different pathways. IGF-I administration severely reduced maternal adiposity in late pregnancy, elicited its effects by substantially improving development of the placental exchange region, which correlated with placental function. We have suggested that the discrete effects of IGF-I and IGF-II stem from distinct interactions of the IGFs with various receptors. Maternal administration of an analogue of IGF-II that selectively interacts with IGF2R (Leu ²⁷-IGF-II), revealed that many of the effects of IGF-II treatment, were mediated by IGF2R, while IGF-I presumably acts through IGF1R. Together, this work has highlighted the major and somewhat complementary roles of maternal IGFs during the first half of pregnancy, in regulating placental development, fetal growth and pregnancy success. Importantly, it indicates the potential use of maternal IGFs in diagnostic and therapeutic approaches to pregnancy complications.Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2007

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.This is the final version of the article. It first appeared from Frontiers via https://doi.org/10.3389/fphys.2016.0003

Assessment of Placental Transport Function in Studies of Disease Programming.

Environmental conditions during pregnancy affect fetal growth and development and program the offspring for poor future health. These effects may be mediated by the placenta, which develops to transfer nutrients from the mother to the fetus for growth. The ability to measure the unidirectional maternofetal transfer of non-metabolizable radio-analogues of glucose and amino acid by the placenta in vivo has thus been invaluable to our understanding of the regulation of fetal growth, particularly in small animal models. Herein, I describe the method by which in vivo placental transfer function can be quantified in the mouse, an animal model widely used in studies of in utero disease programming

Developmental programming of offspring adipose tissue biology and obesity risk.

Obesity is reaching epidemic proportions and imposes major negative health crises and an economic burden in both high and low income countries. The multifaceted nature of obesity represents a major health challenge, with obesity affecting a variety of different organs and increases the risk of many other noncommunicable diseases, such as type 2 diabetes, fatty liver disease, dementia, cardiovascular diseases, and even cancer. The defining organ of obesity is the adipose tissue, highlighting the need to more comprehensively understand the development and biology of this tissue to understand the pathogenesis of obesity. Adipose tissue is a miscellaneous and highly plastic endocrine organ. It comes in many different sizes and shades and is distributed throughout many different locations in the body. Though its development begins prenatally, quite uniquely, it has the capacity for unlimited growth throughout adulthood. Adipose tissue is also a highly sexually dimorphic tissue, patterning men and women in different ways, which means the risks associated with obesity are also sexually dimorphic. Recent studies show that environmental factors during prenatal and early stages of postnatal development have the capacity to programme the structure and function of adipose tissue, with implications for the development of obesity. This review summarizes the evidence for a role for early environmental factors, such as maternal malnutrition, hypoxia, and exposure to excess hormones and endocrine disruptors during gestation in the programming of adipose tissue and obesity in the offspring. We will also discuss the complexity of studying adipose tissue biology and the importance of appreciating nuances in adipose tissue, such as sexual dimorphism and divergent responses to metabolic and endocrine stimuli. Given the rising levels of obesity worldwide, understanding how environmental conditions in early life affects adipose tissue phenotype and the subsequent development of obesity is of absolute importance

Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress

Abstract: The results of different human epidemiological datasets provided the impetus to introduce the now commonly accepted theory coined as ‘developmental programming’, whereby the presence of a stressor during gestation predisposes the growing fetus to develop diseases, such as metabolic dysfunction in later postnatal life. However, in a clinical setting, human lifespan and inaccessibility to tissue for analysis are major limitations to study the molecular mechanisms governing developmental programming. Subsequently, studies using animal models have proved indispensable to the identification of key molecular pathways and epigenetic mechanisms that are dysregulated in metabolic organs of the fetus and adult programmed due to an adverse gestational environment. Rodents such as mice and rats are the most used experimental animals in the study of developmental programming. This review summarises the molecular pathways and epigenetic mechanisms influencing alterations in metabolic tissues of rodent offspring exposed to in utero stress and subsequently programmed for metabolic dysfunction. By comparing molecular mechanisms in a variety of rodent models of in utero stress, we hope to summarise common themes and pathways governing later metabolic dysfunction in the offspring whilst identifying reasons for incongruencies between models so to inform future work. With the continued use and refinement of such models of developmental programming, the scientific community may gain the knowledge required for the targeted treatment of metabolic diseases that have intrauterine origins

Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α\alpha signaling to modify placental resource allocation

Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, $\textit{Pik3ca}$ (encoding PIK3CA also known as p110$\alpha$, $\alpha$/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and $\alpha$/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of $\alpha$/+ fetuses. Despite its defective development, the $\alpha$/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was $\alpha$/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110$\alpha$ deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation.Centre for Trophoblast Research award of a Next Generation Fellowship, Erasmus Exchange scheme scholarshipThis is the author accepted manuscript. The final version is available from the National Academy of Sciences via http://dx.doi.org/10.1073/pnas.160201211

Near to One's Heart: The Intimate Relationship Between the Placenta and Fetal Heart.

The development of the fetal heart is exquisitely controlled by a multitude of factors, ranging from humoral to mechanical forces. The gatekeeper regulating many of these factors is the placenta, an external fetal organ. As such, resistance within the placental vascular bed has a direct influence on the fetal circulation and therefore, the developing heart. In addition, the placenta serves as the interface between the mother and fetus, controlling substrate exchange and release of hormones into both circulations. The intricate relationship between the placenta and fetal heart is appreciated in instances of clinical placental pathology. Abnormal umbilical cord insertion is associated with congenital heart defects. Likewise, twin-to-twin transfusion syndrome, where monochorionic twins have unequal sharing of their placenta due to inter-twin vascular anastomoses, can result in cardiac remodeling and dysfunction in both fetuses. Moreover, epidemiological studies have suggested a link between placental phenotypic traits and increased risk of cardiovascular disease in adult life. To date, the mechanistic basis of the relationships between the placenta, fetal heart development and later risk of cardiac dysfunction have not been fully elucidated. However, studies using environmental exposures and gene manipulations in experimental animals are providing insights into the pathways involved. Likewise, surgical instrumentation of the maternal and fetal circulations in large animal species has enabled the manipulation of specific humoral and mechanical factors to investigate their roles in fetal cardiac development. This review will focus on such studies and what is known to date about the link between the placenta and heart development