Role of Microsomal Prostaglandin E Synthase-1 (mPGES1)-Derived PGE2 in Patency of the Ductus Arteriosus in the Mouse

Abstract

Prostaglandin E 2 (PGE 2 ) 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 (mPGES1Ϫ/Ϫ), we have examined the importance of this enzyme for PGE 2 formation and function. mPGES1Ϫ/Ϫ ductus, unlike WT ductus, contracted little, or not all, to indomethacin in vitro. Coincidentally, as evident from responses to N G -nitro-Larginine 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 mPGES1Ϫ/Ϫ fetuses. Conversely, postnatal closure progressed regularly in mPGES1Ϫ/Ϫ animals thanks to residual PGE 2 originating via mPGES2. We conclude that mPGES1 is critical for PGE 2 formation in the ductus but its loss does not entail compensatory upregulation 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. (Pediatr Res 64: 523-527, 2008) P rostaglandin (PG) E 2 is viewed as the prime agent for prenatal patency of the ductus arteriosus (1). Conversely, PGI 2 is without a role, notwithstanding its occurrence in the vessel and its known importance for vasoregulation elsewhere (2,3). Ductal PGE 2 is formed primarily through the cyclooxygenase-2 (COX2)/microsomal PGE synthase-1 (mPGES1) complex, while little of the compound originates from the COX1/mPGES1 complex and none at all from cytosolic PGES (cPGES). No information is available on microsomal PGE synthase-2 (mPGES2), but evidence from other vascular districts points to its minor function (4). Several findings support this arrangement in the ductus, namely, immunocytochemical data showing a predominant colocalization of COX2 with mPGES1 (5); the increase in COX2 and mPGES1 expression occurring selectively through development (6); the constrictor action of COX2 inhibitors on the ductus, being close or even equal in magnitude to that of a dual COX1/ COX2 inhibitor (7-9); the greater impairment of PGE 2 -based relaxation upon COX2 than COX1 deletion (5) along with the marked curtailment of PGE 2 formation after inhibition of either COX2 or mPGES1 (6,7). Consistent with the preferential operation of the COX2/mPGES1 route for PGE 2 synthesis is also evidence from adult blood vessels (10) and the notion that mPGES1 is catalytically most active among the PGES (11).Despite these facts, previous attempts to prove the actual importance of the COX2/mPGES1 pathway for ductus patency have failed. As shown by others and ourselves (5,12,13), COX2 removal does not result in loss of patency, likely thanks to ...

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

“…Dimensions of the excised KI DA did not change with the MF63 pretreatment ( table 1 ) even though the vessel is dilated in vivo (see below), nor did they differ from those reported earlier for the WT animal [5,6] . Conceivably, DA 'overdilatation' in the treated fetus reflects an active process which is not translated into a morphological alteration.…”

“…In addition, indomethacin elicited the same reaction [5], while, in contrast, deletion of the major PGE synthase in DA, i.e. type 1 microsomal isoform (mPGES1), had no such effect [6] . The idea was, therefore, put forward that failure with COX inhibitors may derive, in part or in full, from the drive upwards of NO.…”

Insights into the Pathogenesis and Genetic Background of Patency of the Ductus Arteriosus

“…Mouse Models with Deletions in the PG Pathway Targeted deletions that reduce the PGE 2 production or function paradoxically do not affect the prenatal ductal patency [60][61][62] but instead may result in impaired DA closure after birth [61][62] . Although the importance of PGE 2 signaling for postnatal DA closure has been known from EP4-deleted and COX-deleted animals for a long time, the explanation for this paradoxical behavior has only recently been elucidated by Yokoyama et al [63] .…”

Therapeutic manipulation of the ductus arteriosus: current options and future prospects

“…The ductus is endowed with a complete, COX and PGE synthase, system, 15 hence making it unrewarding to attempt to replace currently used nonselective inhibitors with the newly developed COX-2 inhibitors. Conversely, as discussed below, a promising lead may be found in the PGE synthase complex when considering that one of its constituents, microsomal PGE synthase-1 (mPGES1), is the prime source for PGE 2 in the ductus 20 and that mPGES1 suppression, unlike suppression of either COX, 13,14 is not followed by NO upregulation. 20,21 Postnatal closure The functional closure of the ductus rests on 2 complementary events, the contractile effect of oxygen on the muscle cells and the lesser influence of relaxant PGE 2 that follows the abrupt cessation of the placental function (i.e., the major source for blood-borne compound) and the waning expression of local PGE 2 receptors including the critical EP 4 subtype.…”

“…Conversely, as discussed below, a promising lead may be found in the PGE synthase complex when considering that one of its constituents, microsomal PGE synthase-1 (mPGES1), is the prime source for PGE 2 in the ductus 20 and that mPGES1 suppression, unlike suppression of either COX, 13,14 is not followed by NO upregulation. 20,21 Postnatal closure The functional closure of the ductus rests on 2 complementary events, the contractile effect of oxygen on the muscle cells and the lesser influence of relaxant PGE 2 that follows the abrupt cessation of the placental function (i.e., the major source for blood-borne compound) and the waning expression of local PGE 2 receptors including the critical EP 4 subtype. 22,23 A considerable effort has been devoted over the years to identify the oxygen sensor and elucidate the mechanism by which its activation is translated into sustained contraction.…”