Regulation of endovascular trophoblast cell development and uterine spiral artery remodeling

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Project Summary / Abstract The oxygen and nutrient demands of a developing fetus increase as gestation progresses. Thus, the vessels, or spiral arteries, that facilitate the transfer of maternal blood to the conceptus must undergo extensive remodeling to ensure sufficient nutrient delivery and successful pregnancy. If vascular remodeling is insufficient and proper blood transfer cannot occur, pregnancy disorders such as preeclampsia, preterm birth, and intrauterine growth restriction can develop and threaten the health of both mother and fetus. Arterial remodeling is complex, as several maternal and extraembryonic cells interact at the maternal interface to regulate the extracellular matrix remodeling, cell loss, and cell invasion necessary for successful placentation. Despite this complexity, one critical mechanism for spiral artery remodeling is invasion of trophoblast cells into the maternal compartment. Previous studies from our lab indicate a critical function of matrix metalloproteinase 12 (MMP12) in regulating trophoblast invasion. However, little is known about the molecular mechanisms of MMP12-mediated trophoblast function. This lack of understanding can be attributed to several factors including difficulties in studying human physiology and interrogating cell populations of interest from tissues ex vivo. Therefore, the studies outlined in this proposal integrate animal models, human tissue samples, and novel approaches to identify critical mechanisms regulating trophoblast invasion and thus, spiral artery remodeling in placentation. Similar to humans, the rat possesses hemochorial placentation with deep trophoblast cell invasion and trophoblast-mediated spiral artery remodeling. Therefore, rat models will be used to determine how MMP12 regulates trophoblast cell function, and trophoblast cells will be isolated from rat placenta as well as first trimester human tissues to identify conserved mechanisms of endovascular trophoblast function. Lentiviral manipulation of blastocysts and embryo transfer will provide a unique opportunity to dissect the molecular mechanisms driving trophoblast invasion. Laser capture microdissection will enable derivation of discrete cell populations from both rat and human placental tissue. Overall, trophoblast invasion is critical to spiral artery remodeling and placentation. Further investigation into mechanisms regulating placental vascular remodeling during pregnancy will aid preventative efforts to detect pregnancy disorders at earlier onset and to develop safe and effective interventions.