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Haploinsufficiency for Adrenomedullin Reduces Pinopodes and Diminishes Uterine Receptivity in Mice¹

Department of Cell and Molecular Physiology,³ Neuroscience Center,⁴ The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

ABSTRACT

Adrenomedullin (AM) is a multifunctional peptide vasodilator that signals through a G-protein-coupled receptor when the receptor, called calcitonin receptor-like receptor (CL), is associated with a receptor activity-modifying protein 2 (RAMP2). We demonstrated previously that haploinsufficieny for each of these genes led to reduced maternal fertility, and that even a modest genetic reduction of AM peptide caused maternal defects in implantation, placentation, and fetal growth. Here, we further demonstrate that Adm^+/– female mice displayed reduced pregnancy success rates that were not caused by defects in folliculogenesis, ovulation, or fertilization. The poor fertility of Adm^+/– female mice could not be rescued by transfer of wild-type blastocysts, which suggested an underlying defect in uterine receptivity. In fact, we found that Adm, Calcrl, and Ramp2 gene expressions are tightly and spatiotemporally regulated in the luminal epithelial cells of the uterus during the estrus cycle and the peri-implantation period. RAMP3, which also generates an AM receptor when associated with CL, had a diametrically opposite expression pattern than that of Adm, Calcrl, and Ramp2 and was most robustly induced in the stroma of the uterus. Finally, we discovered that Adm^+/– female mice have a substantially reduced number of pinopodes on the uterine luminal epithelial surface, which is indicative and possibly causative of the poor uterine receptivity. Taken together, our studies identify a new class of pharmacologically tractable proteins that are involved in establishing uterine receptivity through the regulation of pinopode formation.

adrenomedullin, female fertility, female reproductive tract, gene-targeted mouse models, gene targeting, implantation, pinopodes, uterine receptivity, uterus

¹Supported by the Burroughs Wellcome Fund and National Institutes of Health grant HD046970 to K.M.C.

Correspondence: ²Department of Cell & Molecular Physiology, CB #7545, 6330 MBRB 111 Mason Farm Rd., The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. FAX: 919 966 5230; e-mail: Kathleen_caron{at}med.unc.edu