verbatim): Pharmacological and clinical evidence has implicated prostanoids, arachidonic acid (AA) metabolites produced by cyclooxygenases 1 and 2 (COX-1 and COX-2), in the physiology of the blood vessel. In this proposal, we focus on the ductus arteriosus (DA) as a model for studying the role of prostanoids in vascular remodeling. The DA is an arterial connection in the fetus that directs blood away from the pulmonary circulation and towards the placenta where oxygenation occurs. Permanent closure of the DA depends on a series of structural changes that are independent of the reversible muscular contraction that initially reduces blood flow through this shunt after birth. It has been hypothesized that the DA has an intrinsic tone that is opposed by the dilatory effects of prostanoids such as PGE2 and that a postnatal decrease in levels of circulating prostanoids provides the signal that triggers DA closure. This idea was recently challenged by our observation of mice deficient in the EP4 receptor for PGE2. Contrary to our expectations, we found that the DA in EP4-/- mice remained patent throughout gestation but failed to close after birth, leading to perinatal death. To reconcile the results of previous pharmacological studies with those obtained through our genetic approach, we proposed a model in which EP4 expressed by the DA acts as a sensor that triggers closure of the DA in response to a perinatal drop in circulating levels of PGE2. We propose here to use a combined genetic, molecular, and pharmacological approach to develop a comprehensive molecular model for the mechanism by which the PGE2/EP4 pathway contributes to the events leading to vascular remodeling of the DA at birth. In addition, we propose to use a population of mice in which DA closure occurs in the absence of the EP4 receptor to identify other pathways that contribute to vascular remodeling of the DA. We believe that understanding these mechanisms and pathways will improve our general understanding of the way in which blood vessels are remodeled in specific disease states.
| Loftin, C D; Trivedi, D B; Tiano, H F et al. (2001) Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc Natl Acad Sci U S A 98:1059-64 |
