Novel Functions of Adrenomedullin, Receptor Activity-Modifying Protein 2, and Gpr182 in Cardiovascular Disease and Cancer Public Deposited

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  • March 21, 2019
Creator
  • Kechele, Daniel
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • The multifunctional circulating peptide, adrenomedullin (AM) signaling through its G protein-coupled receptor (GPCR) complex, comprised of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (Ramp2), is required for lymphatic development and embryonic survival, as well as numerous functions in adult cardiovascular physiology. However these functions, especially during adulthood, have not been fully elucidated. Using both gain- and loss-of-function mouse models these studies aimed to further elucidate the roles of AM signaling during cardiovascular homeostasis and tumor progression. Endothelial restoration of Ramp2 is sufficient to rescue the embryonic lethality-associated with global loss of Ramp2. However, the developmental loss of Ramp2 in non-endothelial cells led to spontaneous hypotension, dilated cardiomyopathy, and multi-organ inflammation in adult survivors. Smooth muscle cell- or global-deletion of CLR did not recapitulate these phenotypes, indicating that Ramp2 is likely interacting with other GPCRs, including parathyroid hormone and glucagon receptors, to maintain cardiovascular homeostasis. While AM signaling is essential for lymphatic development and maintenance, it is unclear how AM influences tumor lymphatics. Tumor cells engineered to overexpress or knockdown AM did not alter tumor growth or angiogenesis. High tumor-derived AM caused tumor and lymph node lymphangiogenesis and increased metastasis. While AM is typically considered protective, these data suggest that AM signaling could enhance tumor progression. While CLR/Ramp2 is the canonical AM receptor, it was previously thought that the AM receptor was the orphan GPCR, Gpr182, of which almost nothing is known. Using a knock-in reporter mouse model to map Gpr182 expression in vivo, Gpr182 was enriched in the active stem cells in the small intestine. Gpr182 was dispensable during development and homeostasis, but when challenged with irradiation injury or adenoma model, reduced Gpr182 led to intestinal hyperproliferation during regeneration and enhanced adenoma formation, respectively. Together, these studies demonstrated the importance of endothelial AM signaling during development, the complexity of GPCR/RAMP interactions in vivo, the underappreciated functions of AM signaling in tumor lymphatic metastasis, and the role of Gpr182 as a negative regulator of intestinal proliferation; all of which could represent pharmacological-tractable targets to treat a number of cardiovascular and neoplastic diseases.
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  • In Copyright
Advisor
  • Caron, Kathleen
  • Otey, Carol
  • Rawls, John
  • Burridge, Keith
  • Dudley, Andrew
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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