Genetic mouse models reveal key physiological functions of adrenomedullin signaling Public Deposited

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  • March 21, 2019
  • Dackor, Ryan T.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • Adrenomedullin (AM) is a potent 52-amino acid peptide vasodilator that is involved in a wide variety of physiological processes, including regulation of renal function, neurotransmission, apoptosis and growth. AM peptide levels are elevated in many cardiovascular conditions, including normal pregnancy, septic shock, hypertension, and renal failure. The multitude of conditions associated with elevated AM levels suggests that it serves to maintain physiological homeostasis during various stresses. AM exerts most of its biological functions by promoting increases in the intracellular messengers, cAMP and/or nitric oxide. Recent characterization of AM signaling has identified a unique mechanism of G-protein coupled receptor signaling, mediated by a class of single transmembrane proteins called receptor activity modifying proteins (RAMPs), that have been shown to dictate ligand binding specificity of the calcitonin receptor like receptor (CLR for protein, Calcrl for gene). To date, three RAMP proteins have been identified and it is the association of RAMP2 or 3 with CLR that designates an AM receptor. My research has utilized several lines of gene targeted mice to determine the in vivo role of AM and its signaling components in various physiologic contexts. I show here that mice lacking CLR suffer from extreme hydrops fetalis and die at mid-gestation with severe cardiovascular defects, including small overall heart sizes, thin vascular smooth muscle cell walls and defects in myocardial proliferation and apoptosis. To further examine the role of CLR in cardiac development and physiology, I crossed mice with a floxed Calcrl allele to two cardiomyocyte-specific Cre lines, [alpha]-MHC and cardiac troponin. These mice develop normally and are born at the expected Mendelian ratios. Additionally, echocardiography and histological examination revealed no significant differences in heart structure or function as late as 14 weeks of age. Cardiomyocyte-specific CLR knockouts and control littermates also responded similarly to cardiac challenge in two different disease models: transverse aortic constriction and angiotensin II infusion. A separate study revealed that RAMP2 and RAMP3 have distinct physiological functions from embryogenesis to old age, whereby genetic deletion of Ramp2 results in embryonic lethality while deletion of Ramp3 has no effect on embryonic development or survival. Finally, I used mice heterozygous for the AM gene to show that the AM peptide is required for the normal inflammatory response to LPS-induced septic shock. Collectively, the work presented here provides the first in vivo genetic characterization of several key genes involved in AM signaling during various physiological conditions.
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  • Caron, Kathleen
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  • University of North Carolina at Chapel Hill
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