Mechanistic insights into the development of severe fetal growth restriction

Abstract

Fetal growth restriction (FGR), which most commonly results from suboptimal placental function, substantially increases risks for adverse perinatal and long-term outcomes. The only “treatment” that exists is delivery, which averts stillbirth but does not improve outcomes in survivors. Furthermore, the potential long-term consequences of FGR to the fetus, including cardiometabolic disorders, predispose these individuals to developing FGR in their future pregnancies. This creates a multi-generational cascade of adverse effects stemming from a single dysfunctional placenta, and understanding the mechanisms underlying placental-mediated FGR is critically important if we are to improve outcomes and overall health. The mechanisms behind FGR remain unknown. However, placental insufficiency derived from maldevelopment of the placental vascular systems is the most common etiology. To highlight important mechanistic interactions within the placenta, we focus on placental vascular development in the setting of FGR. We delve into fetoplacental angiogenesis, a robust and ongoing process in normal pregnancies that is impaired in severe FGR. We review cellular models of FGR, with special attention to fetoplacental angiogenesis, and we highlight novel integrin-extracellular matrix interactions that regulate placental angiogenesis in severe FGR. In total, this review focuses on key developmental processes, with specific focus on the human placenta, an underexplored area of research.

The significance of Syndecan 1, a new marker for endothelial dysfunction, in cases of fetal growth retardation

“…Syndecan1 (SDC1) is one of the most important glycocalyx proteoglycans. 8,9 It is highly localized in the syncytiotrophoblasts of chorionic villi and regulates cell signaling by forming a complex with the Vascular Endothelial Growth Factor (VEGF) receptor. SDC1 plays a role in processes such as regulation of vascular permeability, release of nitric oxide, modulation of vascular tone and blood coagulation by regulating VEGF signaling and plays an important role in endothelial cell migration, embryonic development, tumorogenesis and angiogenesis.…”

“…It has functions such as ensuring the integrity of the tissue, preventing the adhesion of leukocytes and platelets and antithrombotic activation. Syndecan1 (SDC1) is one of the most important glycocalyx proteoglycans 8,9 . It is highly localized in the syncytiotrophoblasts of chorionic villi and regulates cell signaling by forming a complex with the Vascular Endothelial Growth Factor (VEGF) receptor.…”

Use of Photoacoustic Imaging to Study the Effects of Anemia on Placental Oxygen Saturation in Normoxic and Hypoxic Conditions

“…In the following weeks, vascular remodeling results in increased perfusion, resulting in improved oxygen and nutrient delivery to the placenta and fetus. Impaired oxygen delivery to the placenta or fetus, such as in cases of maternal hypoxemia or placental insu ciency, can result in severe pregnancy complications, including intrauterine growth restriction (IUGR), developmental anomalies, or fetal demise (2,3). Measurements of fetal or placental oxygen delivery would be useful to evaluate fetal exposure to a hypoxic environment this would also allow for distinguishing between cases of constitutional smallness versus IUGR due to placental insu ciency and other complications of pregnancy.…”

Effects of Intrauterine Growth Restriction (IUGR) on Growth and Body Composition Compared to Constitutionally Small Infants

“…IUGR is defined as a fetus that has failed to reach its growth potential, which can be due to several conditions, but is primarily caused by placental insufficiency and is characterized by impaired oxygen and nutritional supply [17,18]. The underlying cellular and molecular mechanism of fetal growth restriction is still not fully investigated [17,19]. Placentalmediated fetal growth restriction arises mainly from maldevelopment of the placental vascular system [20].…”

“…Several studies showed that impaired fetoplacental angiogenesis is associated with fetal growth restriction [21,22]. Furthermore, recent research investigated novel integrin-extracellular matrix interactions that regulate placental angiogenesis in severe fetal growth restriction [19]. However, further research is needed to investigate the underlying cause of fetal growth restriction as well as prevention and treatment strategies.…”