This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ductus arteriosus (DA) connects the pulmonary artery and aorta in the developing fetus Shortly after birth, the ductus normally closes. Failure to close ductus results in PDA. A decline in circulating prostaglandin E2 (PGE2), preceded by formation of neointimal cushion (NIC) tissue correlates with ductal closure. Thus, the logical assumption would be that EP4 (PGE2 receptor) null mice would have premature DA closure. Surprisingly, EP4 null mice, or cyclooxygenase-2 (COX-2) null mice, instead develop PDA. To understand this paradox of COX2 induced PGE2 signaling, we demonstrated that PGE2/EP4 induced hyaluronan (HA) synthesis is required to prepare the fetal DA for (eventual postnatal) closure and formation of the ductal NIC cells (our published data;JCI, 2006). Recently, we have also demonstrated that PGE2 activates EPAC (Exchange protein activated by cAMP) in the DA during late gestation (unpublished data), and since our previous studies showed that PGE2 also stimulates HA through activation of PKA (our published data;JCI, 2006), it is reasonable to assume the co-ordinated cross-talk among PKA-dependent HA and EPAC-dependent PI3K/AKT for DASMC migration for the induction of neointimal cushion formation. DA closure is directly proportional to smooth muscle cell (SMC) contraction. Generally, vascular-SMC (VSMC) contraction is known to be directly related to phosphorylation of the myosin light chain kinase (MLCK), and protein kinase C-? (PKC?) mediated activation of Erk1/2. Important to our proposed study is that the synthesis of one of the vasodilatory cytokine TNF? is induced during the DA development. Additionaly, the effects of TNF? are implicated in vasodilation of VSMC. Thus TNF? must play an important role in inhibition of VSMC contraction and tone of the DA. The mechanism that assures that the ductal lumen stays open prenatally is as important as the mechanism(s) that close it postnatally. The potential involvement of the HA/CD44 (major HA receptor)-induced signaling that regulate the formation/function of neointimal cells and the role of HA in mediating the effects of TNF? on ductal-SMC contraction was not investigated. Thus, how HA signaling through CD44/COX2/PGE2 pathways regulates the timing of ductal neo-intimal formation and/or expansion to promote closure of the ductus after birth and to assure that it remains patent during prenatal life is the focus of my COBRE research ( Dr.Suniti Misra;PI and Dr. Shibnath Ghatak;Co-PI).
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