Remarkably, female mice with a modest 50% reduction in adrenomedullin gene expression suffer from subfertility due to a variety of reproductive defects including abnormal uterine receptivity, implantation and placentation. Moreover, loss of adrenomedullin from fetal tissues leads to pathological features of preeclampsia in the placenta. Therefore, the precise genetic dosage of adrenomedullin, both from the mother and the fetus, is crucial for establishing and maintaining a normal pregnancy. We are currently investigating the underlying mechanistic basis for the reproductive defects, with a particular focus on characterizing the innate immune response at the maternal-fetal interface. Through our extensive and productive collaborations with clinician scientists and the pharmaceutical industry, we have begun to translate our discoveries to humans by showing that polymorphisms in the genes encoding adrenomedullin signaling are associated with poor pregnancy outcomes and that adrenomedullin peptide can serve as a highly predictive plasma biomarker for severe preeclampsia. In these ways, our studies are contributing to our basic understanding of molecules and processes that govern maternal-to-fetal communication in the placenta and have the potential of providing new clinical diagnostic tools and therapeutic approaches for the amelioration of complications of pregnancy.
- Li M, Yee D, Magnuson T, Smithies O, Caron KM. Reduced maternal expression of adrenomedullin disrupts fertility, placentation and fetal growth in mice. J Clin Invest. 2006 Oct. 116(10):2653-62.
- Li M, Wu Y and Caron KM 2008 Haploinsufficiency for adrenomedullin reduces pinopodes and diminishes uterine receptivity in mice. Biol Reprod. 2008 Dec. 79(6):1169-75.
- Li M, Schwerbrock NMJ, Lenhart PM, Fritz-Six KL, Kadmiel M, Christine KS, Kraus DM, Espenschied ST, Willcockson HH, Mack CP, and Caron KM 2013 Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta. J Clin Invest. 2013 Jun. 123(6):2408-20
- Matson BC, Corty RW, Karpinich NO, Murtha AP, Valdar W, Grotegut CA, Caron KM. Midregional pro- adrenomedullin plasma concentrations are blunted in severe preeclampsia. Placenta. 2014 Sep. 35(9):780-3