The multifunctional peptide vasodilator adrenomedullin (AM) typically signals through a G-protein coupled receptor (GPCR) called calcitonin receptor-like receptor (Calcrl) when the receptor is bound to a novel class of proteins called receptor activity modifying proteins (RAMPs). Using genetically engineered mouse models lacking each of the components of AM signaling, we have found that both maternal and fetal sources of AM signaling are important for orchestrating appropriate implantation and placentation that are required for normal fetal growth. We have shown that maternal AM is involved in the endocrine preparation of the uterus for receptivity to the blastocyst and that a modest 50% reduction in maternal AM levels is sufficient to induce profound reproductive defects associated with poor implantation and placentation. While complete absence of AM and its canonical receptors leads to embryonic lethality due to defects in lymphangiogenesis, we have discovered that fetal AM is also required for the normal branching angiogenesis of the labyrinth layer at mid-gestation. However, we have yet to fully understand the cellular mechanisms through which AM signaling mediates these reproductive effects at the maternal-fetal interface. Surprisingly, not all of the phenotypes in the AM genetic model are recapitulated in the CLR and RAMP2 models, which suggests that the functions of AM may be imparted through receptor-independent pathways or through as yet under-appreciated receptor signaling paradigms. In this regard, AM peptide binds to and potentiates the activity of Complement Factor H, a negative inhibitor of the alternative complement pathway that is important for normal implantation. In addition, AM peptide has also been shown to activate a chemokine receptor, CXCR7. Therefore, studies in this proposal are aimed at elucidating the potential roles of AM as a regulator of the innate immune response at the maternal-fetal interface through canonical, non-canonical or receptor- independent mechanisms. Our goals will be met through the following aims:
Specific Aim 1 is geared toward determining the spatial and temporal expression pattern of AM, Complement Factor H and CXCR7 during the pre-receptive, receptive and refractory uterine phases. Using a novel genetic mouse model and genetically pre-determined blastocyst transfer experiments, we will determine whether fetal and/or maternal sources of AM can influence the expression of these signaling molecules at the maternal-fetal interface.
In Specific Aim 2 we will address whether changes in the genetic dosage of AM signaling can affect the alternative complement pathway at the maternal-fetal interface.
In Specific Aim 3 we will test whether AM signaling through CXCR7 represents a major mechanism for the appropriate remodeling of maternal spiral arteries during implantation. By completing these aims we hope to provide novel insights into the processes that govern the delicate dialogue between mother and fetus and provide a molecular link between trophoblast-derived factors that influence the maternal immune response during implantation.
We have discovered that both maternal and fetal sources of AM signaling are important for orchestrating appropriate implantation and placentation. We hypothesize that AM, acting through non-canonical pathways, represents an important fetal-derived signal for modulating the maternal innate immune response. If we are correct, then we will provide novel insights into the processes that govern the delicate dialogue between mother and fetus and provide a molecular link between trophoblast- derived factors that influence the maternal immune response during implantation.
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|Wetzel-Strong, Sarah E; Li, Manyu; Espenschied, Scott T et al. (2016) Cohort of estrogen-induced microRNAs regulate adrenomedullin expression. Am J Physiol Regul Integr Comp Physiol 310:R209-16|
|Karpinich, Natalie O; Caron, Kathleen M (2015) Gap junction coupling is required for tumor cell migration through lymphatic endothelium. Arterioscler Thromb Vasc Biol 35:1147-55|
|Klein, Klara R; Caron, Kathleen M (2015) Adrenomedullin in lymphangiogenesis: from development to disease. Cell Mol Life Sci 72:3115-26|
|Klein, Klara R; Karpinich, Natalie O; Espenschied, Scott T et al. (2014) Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev Cell 30:528-40|
|Karpinich, Natalie O; Caron, Kathleen M (2014) Apelin signaling: new G protein-coupled receptor pathway in lymphatic vascular development. Arterioscler Thromb Vasc Biol 34:239-41|
|Wetzel-Strong, Sarah E; Li, Manyu; Klein, Klara R et al. (2014) Epicardial-derived adrenomedullin drives cardiac hyperplasia during embryogenesis. Dev Dyn 243:243-56|
|Matson, B C; Corty, R W; Karpinich, N O et al. (2014) Midregional pro-adrenomedullin plasma concentrations are blunted in severe preeclampsia. Placenta 35:780-3|
|Matson, Brooke C; Caron, Kathleen M (2014) Uterine natural killer cells as modulators of the maternal-fetal vasculature. Int J Dev Biol 58:199-204|
|Kraus, Daniel M; Feng, Liping; Heine, R Phillips et al. (2014) Cigarette smoke-induced placental adrenomedullin expression and trophoblast cell invasion. Reprod Sci 21:63-71|
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