Role of microsomal prostaglandin E synthase-1 (mPGES1)-derived PGE2 in patency of the ductus arteriosus in the mouse.
Prostaglandin E2 (PGE2) plays a key role in the ductus arteriosus, prenatally by maintaining patency and postnatally by promoting tissue remodeling for closure. Here, by using near-term mouse fetuses with (wild-type, WT) and without microsomal PGE synthase-1 (mPGES1-/-), we have examined the importance of this enzyme for PGE2 formation and function. mPGES1-/- ductus, unlike WT ductus, contracted little, or not all, to indomethacin in vitro. Coincidentally, as evident from responses to NG-nitro-L-arginine methyl ester and zinc photoporphyrin, the mutant showed no significant enhancement of nitric oxide (NO)- and carbon monoxide (CO)-based relaxation. mPGES1 suppression differs, therefore, from cyclooxygenase (COX) suppression, whether genetically or pharmacologically induced, where NO is markedly up-regulated. In vivo, the ductus was patent, albeit occasionally with a narrowed lumen, in all mPGES1-/- fetuses. Conversely, postnatal closure progressed regularly in mPGES1-/- animals thanks to residual PGE2 originating via mPGES2. We conclude that mPGES1 is critical for PGE2 formation in the ductus but its loss does not entail compensatory up-regulation of other relaxing mechanisms. Accordingly, an mPGES1 inhibitor stands out as a prospective better tool, compared with the currently used COX inhibitors, for the management of premature infants with persistent ductus.
Baragatti
Barbara
B
Scuola Superiore Sant'Anna and Institute of Clinical Physiology CNR, Pisa 56100, Italy.
Sodini
Daria
D
Uematsu
Satoshi
S
Coceani
Flavio
F
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004373:Ductus Arteriosus / Q000201:enzymology* / Q000503:physiopathology; D004374:Ductus Arteriosus, Patent / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005865:Gestational Age; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014654:Vascular Patency
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D011524:Protoporphyrins; D012333:RNA, Messenger; C017803:zinc protoporphyrin; D009569:Nitric Oxide; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin