Folliculogenesis is under the control of growth factors and two pituitary gonadotropin hormones; follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These heterodimeric glycoproteins bind in the ovary to specific G-protein coupled receptors, FshR and LhR respectively, to facilitate the growth and differentiation of ovarian cells and also to control the production of the two steroid hormones estradiol and progesterone, for review see [1, 2].
Amongst the several autocrine and/or paracrine growth factors produced by the follicle itself, prostaglandins are critical for multiple stages of reproduction [3, 4]. Mice lacking the cyclo-oxygenase-2 (Cox-2) gene encoding the rate limiting step in prostaglandin synthesis, show pre-implantation deficiencies throughout ovulation and fertilization . This phenotype is also seen in the absence of prostaglandin E2 (PGE2) receptor EP2 . A surge in LH levels in granulosa cells of pre-ovulatory follicles induces expression of Cox-2 and EP2 , while elevated PGE2 in turn, stimulates cumulus expansion by elevating cAMP . It has also been shown that PGE2 increases expression of the aromatase Cyp19A1 gene, the key gene in estrogen biosynthesis in granulosa cells , as well as acting as a luteotrophic component to stimulate luteal progesterone secretion through a cAMP-mediated pathway in both human and ruminants . Besides PGE2, prostaglandin PGF2α secretion via cyclo-oxygenase COX-1 expression and the action of its receptor FP, also plays an important role in diminishing progesterone levels and stimulating luteolysis, a crucial stage in inducing labor and pup delivery during parturition in human and mice [11, 12]. Whereas PGE2 and PGF2α are both involved in regulating ovulation, luteinization, luteolysis and fertility [13–16], the role(s) of PGD2 signaling in folliculogenesis and ovarian physiology is not precisely understood.
PGD2 has been implicated as a signaling molecule in the mediation or regulation of various biological processes such as platelet aggregation, broncho-constriction and allergic diseases [17, 18], whilst also being identified as a partner of the embryonic sex-determining male cascade [19, 20]. Secreted PGD2 interacts with two receptors: (i) the specific membrane-bound DP receptor (DP1) associated with adenylcyclase and intracellular cAMP production [21, 22], and (ii) chemo attractant receptor Th2 (CRTH2) cells (DP2) which is coupled to Ca2+ signaling. A metabolite of PGD2, PGJ2, has also been shown to bind the peroxisome proliferator-activated receptor PPARγ a member of the orphan nuclear receptor superfamily implicated in key female reproductory roles . PGD2 is produced by two prostaglandin D synthases (Pgds) responsible for mediating the final regulatory step in the biosynthetic pathway of PGD2 production : (i) the lipocalin-type Pgds (L-Pgds), a member of the lipocalin ligand-carrier protein family [24, 25] and (ii) the hematopoietic-type Pgds (H-Pgds) or GSH-requiring enzyme .
The L-Pgds transcript initially found in the brain , represents one of the ten most abundant transcripts in the cortex, hypothalamus and pituitary gland . However, it is not expressed in either the embryonic or the adult ovary [20, 29, 30] whereas H-Pgds is expressed in the embryonic gonad of both sexes (submitted data). H-Pgds is a cytosolic protein responsible for the biosynthesis of PGD2 in immune and inflammatory cells such as mast cells or Th2 cells, and is also expressed in the spleen, thymus, skin and liver , in the microglia where H-Pgds-produced PGD2 is responsible for the neuroinflammation associated with brain injury and neurodegenerative diseases , as well as in trophoblasts, uterine epithelium and endometrial glands at the implantation site of the human decidua . H-Pgds expression was also found in the hypothalamus-pituitary axis of hens and has been associated with high egg production . Recently, PGD2 produced by H-Pgds and its metabolite PGJ2 have been shown to induce transcription of the Lhb subunit gene in the primary culture of chicken anterior pituitary cells, via the PPARα and PPARγ signaling pathways . On the other hand, a stimulatory effect of PGD2 on progesterone secretion has been found in vitro in isolated human corpus lutea . However, the precise H-Pgds expression profile and function of PGD2 signaling in the adult ovary remain unknown.
Here, we report the characterization and ovarian localization of H-Pgds mRNA and provide evidence of a role of H-Pgds-produced PGD2 signaling in the FSH signaling via the increase of FshR and LhR receptor expression, leading to activation of steroidogenic Cyp11A1 and StAR gene expression and progesterone secretion. We found that in vivo inhibition of H-Pgds activity failed to modify PGE2 and PGF2α synthesis in the ovary and also identify a role for H-Pgds-produced PGD2 in follicular growth regulation. Our results provide evidence that PGD2 signaling is a modulator of the differentiation and steroidogenic activity of granulosa cells.