An Aldose Reductase with 20α-Hydroxysteroid Dehydrogenase Activity Is Most Likely the Enzyme Responsible for the Production of Prostaglandin F2α in the Bovine Endometrium

Abstract

Prostaglandins are important regulators of reproductive function. In particular, prostaglandin F2␣ (PGF 2␣ ) is involved in labor and is the functional mediator of luteolysis to initiate a new estrous cycle in many species. These actions have been extensively studied in ruminants, but the enzymes involved are not clearly identified. Our objective was to identify which prostaglandin F synthase is involved and to study its regulation in the endometrium and in endometrial primary cell cultures. The expression of all previously known prostaglandin F synthases (PGFSs), two newly discovered PGFS-like genes, and a 20␣-hydroxysteroid dehydrogenase was studied by Northern blot and reverse transcription PCR. These analyses revealed that none of the known PGFS or the PGFS-like genes were significantly expressed in the endometrium. On the other hand, the 20␣-hydroxysteroid dehydrogenase gene was strongly expressed in the endometrium at the time of luteolysis. The corresponding recombinant enzyme has a K m of 7 M for PGH 2 and a PGFS activity higher than the lung PGFS. This enzyme has two different activities with the ability to terminate the estrous cycle; it metabolizes progesterone and synthesizes PGF 2␣ . Taken together, these data point to this newly identified enzyme as the functional endometrial PGFS.Prostaglandins are local mediators acting through paracrine or autocrine mechanisms. Prostaglandins are produced from arachidonic acid liberated from phospholipid stores through the action of phospholipases. Arachidonic acid is then converted into prostaglandin H 2 (PGH 2 ), 1 the common precursor of all prostaglandins, through the cyclooxygenase and peroxydase activities of prostaglandin H synthase (PGHS). There are two PGHS: PGHS1 and PGHS2. These enzymes (also known as Cox-1 and Cox-2), which have been identified some 10 years ago, are still extensively studied. Because PGH 2 is the common precursor of all subtypes of prostaglandins and because these prostaglandin isotypes cause different and even opposing actions, the pathways leading to their individual formation need to be identified.Prostaglandin F2␣ (PGF 2␣ ) is involved in several physiological processes including pressure regulation in the eye (1), vasoconstriction (2), and renal filtration (3). It is associated with diseases such as diabetes (4), osteoporosis (5, 6), and menstrual disorder (7). However, it is mostly known for its effect on the female reproductive system. In mice, gene knockout of the FP receptor (the receptor for PGF 2␣ ) leads to a failure in the initiation of labor (8). For most mammalian species, the production of PGF 2␣ by the uterus is involved in the regulation of the ovarian cycle. This prostaglandin acts on the corpus luteum, initiating its regression (luteolysis) and leading to termination of the estrous cycle or of pregnancy (reviewed in Ref. 9). The regulation of PGF 2␣ production at the critical period of luteolysis or recognition of pregnancy has been studied extensively in ruminants. In cattle, PGF 2␣ is mainly synthesized by epit...

Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion

“…Since this study group has previously detected PGF 2a in spent media at 24 h of bovine oocyte maturation (Marei et al, 2010), this suggests that PGFS in COC belong to a different isoform. Other enzymes like AKR1B5 have been identified as functional PGFS in bovine endometrium (Madore et al, 2003) and may be functional in COC as well. The PGFS isoforms in COC and the role of PGF 2a during oocyte maturation will require further investigation.…”

“…Three forms of PGES have been identified (Kudo and Murakami, 2005): PTGES1 (or the microsomal PGES-1) colocalized with PTGS2 (Arosh et al, 2002); PTGES2 (or the microsomal PGES-2) coupled to both PTGS1 and PTGS2 (Murakami et al, 2003); and PTGES3 (or the cytosolic PGES) functionally linked to PTGS1 (Tanioka et al, 2000). On the other hand, PGF synthases are present in multiple isoforms, which belong to C members (AKR1C1, AKR1C3, AKR1C4) or B members (such as AKR1B5) of aldo-keto reductase family 1 (Jez et al, 1997;Madore et al, 2003).…”

Evaluation of the uterine environment early in pregnancy establishment to characterise cows with a potentially superior ability to support conceptus survival

“…Similarly, PGES and PGHS2 expression was lower in the endometrium of pregnancies with smaller conceptuses. PGHS2 is a rate-limiting enzyme in the prostaglandin pathway that catalyses the transformation of arachidonic acid into the common prostaglandin precursor PGH 2 which can then be converted to PGE 2 by PGES or to PGF 2a by PGFS (Madore et al 2003). PGHS2 expression in sheep and cattle is transient early in the oestrous cycle and requires progesterone exposure for at least 10 days (Charpigny et al 1997;Arosh et al 2002).…”

Genes Regulating Maternal Recognition of Pregnancy in Domestic Animals: an Update

“…All these isoforms belong to the AKR1C subfamily, except from Trypanosoma, which belongs to the AKR5A subfamily. In bovine, six isoforms of PGFS, viz., PGFS1, PGFS2, DDBX, PGFS like 1 (PGFSL1), PGFSL2 and 20 -HSD have been identified (Madore et al 2003). A new isoform, AKR1B5 possessing aldoreductase activity has been implicated as the most probable enzyme responsible for the production of PGF 2 in bovines (Madore et al 2003).…”