Cyclooxygenase‐1 and cyclooxygenase‐2 in the mouse ductus arteriosus: individual activity and functional coupling with nitric oxide synthase

Abstract

1 Prenatal patency of the ductus arteriosus is maintained by prostaglandin (PG) E 2 , conceivably in concert with nitric oxide (NO). Local PGE 2 formation is sustained by cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2), a possible exception being the mouse in which COX1, or both COXs, are reportedly absent. Here, we have examined the occurrence of functional COX isoforms in the nearterm mouse ductus and the possibility of COX deletion causing NO upregulation. 2 COX1 and COX2 were detected in smooth muscle cells by immunogold electronmicroscopy, both being located primarily in the perinuclear region. Cytosolic and microsomal PGE synthases (cPGES and mPGES) were also found, but they occurred diffusely across the cytosol. COX1 and, far more frequently, COX2 were colocalised with mPGES, while neither COX appeared to be colocalized with cPGES. 3 The isolated ductus from wild-type and COX1À/À mice contracted promptly to indomethacin (2.8 mm). Conversely, the contraction of COX2À/À ductus to the same inhibitor started only after a delay and was slower. 4 N G -nitro-l-arginine methyl ester (l-NAME, 100 mm) weakly contracted the isolated wild-type ductus. Its effect, however, increased three-to four-fold after deleting either COX, hence equalling that of indomethacin. 5 In vivo, the ductus was patent in all mice foetuses, whether wild-type or COX-deleted. Likewise, no genotype-related difference was noted in its postnatal closure. 6 We conclude that the mouse ductus has a complete system for PGE 2 synthesis comprising both COX1 and COX2. The two enzymes respond differently to indomethacin but, nevertheless, deletion of either one results in NO upregulation. PGE 2 and NO can function synergistically in keeping the ductus patent.

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

“…The mPGES1Ϫ/Ϫ fetus differs from fetuses lacking COX1 or COX2 whose duct presents a marked up-regulation of NO (5). Not fortuitously, the latter mutants have always an open ductus without any sign of constriction (5). The question, then, can be raised on why is the NO system unevenly affected by mPGES1 versus COX deletion, with the lesser activation occurring somewhat paradoxically in a situation (i.e.…”

“…Whatever its mechanism(s), the intervening compensation is expectedly limited and, in fact, appears inadequate in the few mPGES1Ϫ/Ϫ fetuses showing a constricted ductus. The mPGES1Ϫ/Ϫ fetus differs from fetuses lacking COX1 or COX2 whose duct presents a marked up-regulation of NO (5). Not fortuitously, the latter mutants have always an open ductus without any sign of constriction (5).…”

“…As shown by others and ourselves (5,12,13), COX2 removal does not result in loss of patency, likely thanks to compensation from COX1-derived PGE 2 and nonPG agents such as nitric oxide (NO) and carbon monoxide (CO). Indeed, COX2 removal, even if limited to a single allele, is followed by selective up-regulation of NO (5,14).…”

“…As shown by others and ourselves (5,12,13), COX2 removal does not result in loss of patency, likely thanks to compensation from COX1-derived PGE 2 and nonPG agents such as nitric oxide (NO) and carbon monoxide (CO). Indeed, COX2 removal, even if limited to a single allele, is followed by selective up-regulation of NO (5,14). An additional complication in addressing this issue is that PGE 2 not only sustains patency of the ductus in utero, but also promotes its closure after birth (9,15,16).…”

Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus

“…For instance, COX-2 is barely detected in the DA of fetal pig, but more dominantly regulates DA tone in fetal lamb by expressing it in ECs [43]. Another study found that there is a cooperative interaction between PGE 2 and NO, an endothelial-derived relaxation factor (EDRF) [44]. Several studies showed that NO is more potent than PGE 2 in the preterm DA, whereas the opposite relationship is seen at term [45][46][47].…”