Discerning the Role of Prostaglandins in Ductus Arteriosus Remodeling Public Deposited

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  • March 20, 2019
Creator
  • Gruzdev, Artiom
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The ductus arteriosus (DA) is a fetal pulmonary bypass shunt that constricts and permanently remodels during the transition from fetal to adult circulation. Prostaglandin E2 (PGE2) is potent mediator of numerous physiological responses both in homeostasis and disease state. PGE2 play a vital role in DA maturation and closure, although the exact molecular role is unclear. We attempt to discern the nature of PGE2 involvement in DA maturation and closure. Here we generate a conditional null allele of the prostaglandin E receptor 4 (EP4), which has been previously shown to be responsible for PGE2 signaling in the DA. Utilizing various tissue specific Cre recombinase transgenes, we have shown that EP4 expression on the neural crest derived smooth muscle cells of the DA is critical for proper DA closure. We have also shown that endothelial expression of the PGE2 vasodilatory receptors (EP4 and EP2) is non-essential for DA closure or vascular development. Genome wide expression profiling of the wildtype DA and EP4 deficient DA were used to assess the transcriptional consequences of PGE2/EP4 signaling in the DA. Differentially expressed genes in the wildtype DA indicate that EP4 receptor expression leads to the up-regulation of numerous cytoskeletal genes. The relative minor increase (<2 fold) of numerous cytoskeletal genes may explain why the wildtype and EP4 deficient DA appear morphologically similar in utero but have antithetical fates after birth. Here we also document the existence of a prostaglandin-independent mechanism of DA maturation and closure in mice. Selective mating generated a recombinant inbred (RI) mouse strain that undergoes DA maturation and closure without any contribution from prostaglandin signaling. Single locus inheritance of patent ductus arteriosus (PDA) in common inbred strains (CIS) seemed at odds with the complex inheritance pattern of PDA in larger animals, but the RI strain indicates that DA closure in non-CIS mice is also a complex trait. The study of both prostaglandin-dependent DA closure of CIS mice and prostaglandin-independent DA closure of RI mice provides a mouse model for understanding the complex trait of larger animals.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology."
Advisor
  • Koller, Beverly H.
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  • Chapel Hill, NC
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  • Open access
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