Investigating a potential cardio-placental signaling axis

Project Summary The placenta is a transient, vascular organ necessary for in utero gas, nutrient, waste exchange in the majority of mammals. Placental dysfunction may lead to hypertensive disorders of pregnancy, fetal growth restriction, or intrauterine fetal demise in humans. In mice and humans, congenital cardiac defects are associated with placental insufficiency. In mice, endothelial cells from the allantois generate a highly branched exchange interface with the maternal circulation in a region termed the labyrinth. The molecular pathways that pattern the labyrinth remain poorly characterized. As the embryo develops, its metabolic demands change, and the number of placental vessels appears to increase accordingly. However, signals from the embryo proper that may communicate its oxygen and nutritional requirements remain obscure. I have deleted Endoglin (Eng), an endothelial BMP10 co-receptor, in the labyrinth using Hoxa13-Cre and found it to be lethal in midgestation. BMP10, secreted by the developing heart and liver, acts on ENG and the TGF-β/BMP type I receptor ALK1 on ECs to promote activation of SMAD1/5/8. Histologically, Eng mutant placentas have fewer, narrower fetal vessels than controls, and these vessels appear poorly perfused. Therefore, I hypothesize that ENG and ALK1 in placental ECs function to promote angiogenesis in response to BMP10 secreted by cardiomyocytes. Through this project, I will use in vivo mouse genetic tools to understand the function of ENG in the labyrinth, as well as assess the requirement for a BMP10 signal from the embryo to instruct placental vascularization. In aim 1, I will identify the primary deficit in Hoxa13-Cre; Eng fl/- placentas through morphometric, histologic, and transcriptomic analyses. In aim 2, I will determine whether ENG, along with ALK1, promotes activation of SMAD1/5/8 in placental ECs in response to cardiac-derived BMP10. Together, these experiments will enhance our understanding of how placental development is regulated and informed by the embryo proper, which may have implications for placental insufficiency and congenital heart disease in humans.