Regulation of Fetal Growth through Placental SIRT1 Expression

Intrauterine fetal growth restriction (IUGR) refers to a serious complication of pregnancy, in which the developing fetus does not achieve its full growth potential in utero. IUGR affects up to 7% of all pregnancies and currently this disorder has no treatment or cure, despite recognizing placental dysfunction as the underlying cause of disease. IUGR often requires pre-term delivery in order to minimize fetal morbidity and mortality. The iatrogenic effects of this intervention collectively are responsible for a significant proportion of admissions to our neonatal intensive care units. Behind these disappointing statistics, however, lies a wealth of new knowledge defining the molecular basis of human placental development and pathology. We now know that key elements in the pathophysiology of IUGR include: 1) inadequate placental invasion of the uterine wall; 2) hypoxia and initiation of oxidative stress within the placenta, and; 3) poor feto-placental vascular development. Sirtuin 1 (SIRT1), a class III histone deacetylase, is widely studied in cancer biology where it has been characterized to play important roles in tumor cell invasion, cytoprotection against hypoxic insults and vascular remodeling and angiogenesis. Despite the striking similarities between the known functions of SIRT1 and fundamental events in placental development, the potential role of SIRT1 within the placenta and its impact on pregnancy outcome have not yet been fully explored. We postulate that SIRT1 is an important stress-response protein within the placenta that modulates feto-placental vascular development. Further, we speculate that hypomorphic expression of placental SIRT1 may compromise normal placental development, resulting in compromised fetal growth.

Using a combination of methods, including human placenta cell culture, a SIRT1 knock out mouse model and placenta biopsies from pregnancies complicated by IUGR, we have been able to identify SIRT1 as an important placental protein capable of regulating several vital functions of this organ. Specifically we have determined that SIRT1 is required for normal placental invasion of the uterine wall and establishment of appropriate feto-placental vascularization. Further, we have been able to demonstrate that placentas from babies with IUGR demonstrate decreased SIRT1 expression. Taken together, our results indicate that insufficient SIRT1 expression within the placenta may play a causal role in the development of IUGR. Ongoing studies in the lab are investigating SIRT1 as a therapeutic target for the prevention and/or treatment of IUGR.