The placenta serves as the conduit for communication between the mother and fetus during pregnancy. To ensure that the growing fetus has access to sufficient oxygen and nutrients, the spiral arteries that supply blood to the endometrium must undergo remodeling. Poor remodeling leads to preeclampsia, a common and life threatening complication of pregnancy. Currently, it is unclear exactly which factors govern spiral artery remodeling. Using transgenic mice, Manyu Li and colleagues demonstrated that fetal expression of the peptide adrenomedullin and its receptor is required for recruitment and activation of uterine natural killer cells (uNKs) to the placenta to facilitate remodeling of maternal spiral arteries. In the accompanying images they used scanning electron microscopy to examine vascular corrosion casts of the maternal placental vasculature at low power (top panels) and higher magnification (bottom panels). Compared to wild type mice (left), mice lacking adrenomedullin (right) exhibited wider spacing between the maternal blood sinuses, the area in which the maternal blood comes into contact with the fetus, which is indicative of reduced branching of fetal labyrinth vessels. These findings demonstrate that fetal-derived adrenomedullin plays a critical role in pregnancy-associated vascular remodeling.
The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.
Manyu Li, Nicole M.J. Schwerbrock, Patricia M. Lenhart, Kimberly L. Fritz-Six, Mahita Kadmiel, Kathleen S. Christine, Daniel M. Kraus, Scott T. Espenschied, Helen H. Willcockson, Christopher P. Mack, Kathleen M. Caron