A Paradigm for Investigation of the Placentation Site
A central focus of placentation research is understanding pregnancy-associated restructuring of uterine spiral arteries, the conduit for the embryo/fetus access to maternal nutrients. We approach this important developmental process by investigating molecular mechanisms controlling trophoblast stem cell differentiation with the goal of identifying conserved regulatory networks. Importantly, these insights are tested in vivo using genetically and environmentally manipulated animal models.
Hemochorial placentation occurs in many mammalian species including primates and rodents. It ensures the most intimate contact between maternal and embryonic compartments and requires specialized adjustments. Among these adjustments is the need for extensive remodeling of the maternal uterine spiral arteries. Uterine vascular modifications are required for the delivery of nutrients to the fetus. Disruptions in this fundamental process lead to diseases of pregnancy and placentation, and result in impaired nutrient transport to the fetus, including the delivery of oxygen. Hypoxemia leads to a range of disruptive events within the fetus that have potentially long-lasting postnatal impacts on health and disease.
Mechanisms controlling uterine vascular remodeling remain poorly understood. Central to the vascular remodeling process is a specialized population of trophoblast cells referred to as invasive trophoblast or as extravillous trophoblast. The purpose of this project is to elucidate conserved regulatory processes controlling development of the extravillous trophoblast cell lineage. The rat is used as an experimental model because it exhibits deep intrauterine trophoblast invasion and extensive uterine spiral artery remodeling. These events are remarkably similar in rat and human placentation. Our experimental effort utilizes in vitro models for trophoblast development, including rat and human trophoblast stem cells. Hypotheses generated from the in vitro analyses are tested in vivo using the genetically and environmentally manipulated rat as a model.