Kuei-Yang Hsiao1, Meng-Hsing Wu2 and Shaw-Jenq Tsai1
Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101, Taiwan
Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101, Taiwan
Endometriosis is one of the most common gynecological diseases, affecting approximately 10 % of women in reproductive age. It is characterized as the presence of endometrial-like glands and stroma outside the uterus, commonly on the pelvic peritoneum and ovaries. The major symptoms of endometriosis include pelvic pain, dysmenorrhea, dyspareunia, and infertility. During the past decade, intensive investigations on molecular mechanisms responsible for the pathological processes of endometriosis have been conducted. Although many factors have been reported to be involved in these processes, prostaglandin E2 (PGE2) no doubt represents as one of the most critical regulators of all. Accumulating data demonstrate that PGE2 controls many critical functions, such as steroidogenesis, angiogenesis, proliferation, and immune suppression that contribute to the pathogenesis of endometriosis. Herein, we will summarize the most up-to-date information regarding the functional roles of PGE2 in the development and maintenance of endometriosis.
Although the etiology of endometriosis remains unclear, there are several hypotheses proposed including retrograde menstruation theory, embryonic rest theory, coelomic metaplasia theory, and new combined theory [1–5]. Among these, Sampson’s retrograde menstruation theory is the most accepted one in which it states that the origin of endometriosis is caused by implanted cast-off endometrial tissues, the retrograde menstruation [3, 4]. Several clinical observations, which described that women with cervical or vaginal obstruction have higher risk of developing endometriosis, are in line with this hypothesis [6–8]. In addition, an animal model of baboon showed that the ligation of cervices increases the incidence of endometriosis . A more convincing evidence is that endometriosis is observed exclusively in species that menstruate . Nevertheless, retrograde menstruation theory is insufficient to explain why only 5–10 % of women with reflux menstruation developed endometriosis when 90 % of women in reproductive age have retrograde menstruation . Furthermore, before the infiltration of vasculature, the retrograded tissues have to escape from the surveillance of immune system, gain the capacity of steroidogenesis (because endometrial cells are highly dependent on estrogen), and establish a self-support system to maintain proliferation to survive in the ectopic sites. Therefore, it is clear that other local or even epigenetic factors must exist to contribute to the pathological processes of this disease. It is obvious that we cannot discuss all the factors involved in endometriosis pathogenesis; therefore, in this review chapter, we will primarily focus on the functional roles of prostaglandin E2 (PGE2) and some other factors that are involved in the regulation of PGE2biosynthesis.
9.2 Biosynthesis of PGE2
Prostaglandins, a group of biologically active long-chain fatty acids derived from arachidonic acid, are short-lived eicosanoids that are produced locally in response to numerous stimuli. PGs regulate numerous physiological and pathological processes including but not limited to inflammation, reproduction, respiration, angiogenesis, coagulation, photo-sensing, sleep and awakeness, stem cell generation, and cancer progression [12–16]. In mammals, every cell can synthesize one or more kinds of PGs. The synthesis of PGs involves multiple enzymes and sequential processes. First, it begins with the cleavage of arachidonic acid from diacylglycerol and phospholipids by phospholipase C and A2 (PLC and PLA2), respectively (Fig. 9.1). Then prostaglandin H synthase-1 and synthase-2 (also known as cyclooxygenase-1/cyclooxygenase-2, COX-1/COX-2) convert arachidonic acid to common prostaglandin precursor PGH2. This enzymatic reaction is the rate-limiting step in the biosynthesis of the 2-series of PGs (PGD2, PGE2, PGF2α, PGI2, PGJ2, and thromboxane A2). Third, a group of PG synthases, such as microsomal PGE synthase (mPGES) and PGF synthases, act on PGH2 to produce PGE2 and PGF2α, respectively [17–19]. These enzymes coordinate with preferred partners in specific tissue to produce PGs. For example, in the process of PGE2 synthesis, cytosolic PGES (cPGES) and COX-1 account for constitutive production of PGE2 [19, 20], while the coupling of mPGES-1 and COX-2 is responsible for inflammation-induced PGE2 production . As is the rule for locally acting lipid mediators, PGE2 is not stored but rapidly metabolized once synthesized. The major enzymes responsible for the rapid (within minutes) inactivation of PGE2 are the cytosolic enzymes 15-ketoprostaglandin Δ13-reductase and 15-hydroxyprostaglandin dehydrogenase (15-PGDH).
Biosynthesis of prostaglandin E2. Membrane-bound phospholipids, such as diacylglycerol and phospholipids, are cleaved by phospholipase C and A2 (PLC, PLA2) to yield arachidonic acid, the common precursor of all PGs. Prostaglandin G/H synthase (cyclooxygenase, COX-1/COX-2) then converts arachidonic acid into PGH2, which is further metabolized by microsomal PGE synthase (mPGES) to produce PGE2. PGE transporter (PGT) and multidrug resistance-associated protein 4 (MRP4) are responsible for the uptake and secretion of PGE2, respectively
9.3 Source of PGE2 in Endometriosis
Early in the mid-1980s, it was discovered that concentrations of PGE2 are elevated in the peritoneal fluid collected from women with endometriosis compared to that derived from otherwise healthy women . Later, it became clear that the majority of PGE2 comes from two cell types—peritoneal macrophages and endometriotic stromal cells [22–25]. Macrophages are the major immune cells recruited to the sites where endometriotic tissues reside within first few hours and it has been found that women with endometriotic lesion have more macrophages [26, 27], especially the activated macrophages . COX-2 was overexpressed in peritoneal macrophages from women with endometriosis while COX-1 was expressed at very low level and elevated COX-1 is only seen in the severe stage of endometriosis. It should be noted that COX-2 levels are undetectable in monocytes (precursor of macrophages) isolated from peripheral blood regardless of their stages , indicating that local modulators in the peritoneal cavity promote COX-2 overexpression. Proinflammatory cytokines are commonly elevated in the peritoneal fluid from women with endometriosis  and are potentially responsible for COX-2 induction. Indeed, PGE2, tumor necrosis factor-α (TNF-α), and interlukin-1β (IL-1β) have been demonstrated to promote the expression of COX-2 in peritoneal macrophages . This provides evidence to demonstrate that overproduction of PGE2 by peritoneal macrophages in women with endometriosis is likely due to the activation of COX-2 by a group of proinflammatory cytokines in the peritoneal fluid.
In parallel to macrophages, ectopic endometriotic stromal cells also produce high levels of PGE2 [22, 23, 25]. Phospholipase A2 was found to increase in lesion tissues [29, 30], and mPGES was elevated in both epithelial and stromal cells from women with endometriosis [29, 31]. These elevated PLA2 and mPGES work together with the upregulated COX-2 to increase PGE2 production.
Aberrant expression of COX-2 in endometriotic stromal cells has been reported by several groups [22, 23, 25]. However, one intriguing phenomenon is that although the ectopic endometriotic tissue consists of the same genetic backgrounds as the eutopic endometrium, it possesses distinct biochemical nature compared to its eutopic counterpart. It has been shown that ectopic stromal cells are at least 100 times more sensitive to IL-1β treatment than eutopic endometrial stromal cells in terms of COX-2 expression. The distinct sensitivity is due to increased transcriptional activity of COX-2 promoter in ectopic but not eutopic endometrial stromal cells . Because endometriosis is a chronic inflammatory disease and many proinflammatory cytokines, including IL-1β, are elevated in the peritoneal fluid, increased sensitivity enables ectopic endometriotic stromal cells to respond to the level of proinflammatory cytokines that eutopic endometrial stromal cells normally do not respond. This phenomenon may explain why COX-2 and, to some extent, its downstream target genes are consistently overexpressed in ectopic endometriotic tissues.
The underlying molecular mechanism responsible for the increased sensitivity of ectopic stromal cells to stimuli is an area of interest to be investigated because it may provide important information for designing new treatment regimens. Recent studies reveal that predisposition to hypoxic stress may account for the distinct responses of ectopic endometriotic cells. The retrograded tissues encountered hypoxic stress before the formation of new blood vessels in the ectopic site. Typically, cells sense the hypoxia via an oxygen-dependent hydroxylation on hypoxia-inducible factors (HIFs). There are two kinds of HIF members: the α and β subunits, both of which are constitutively transcribed and translated but undergo differential posttranslational modifications. Under normoxic condition, the α subunit undergoes hydroxylation at two proline residues (Pro402 and Pro564), which ultimately results in 26S proteasome-mediated degradation of HIF-α protein . In response to hypoxia, the α subunit accumulates due to the lack of oxygen-induced hydroxylation and degradation. In contrast, the β subunit does not respond to oxygen-dependent degradation and is constitutively expressed. Thus, the level of α subunit determines the gene expression profile of a cell. In endometriotic stromal cells, levels of HIF-1α mRNA and protein were elevated compared to the eutopic endometrial stromal cells . Elevation of HIF-1α protein or treatment with hypoxia causes the downregulation of dual-specificity phosphatase-2 (DUSP2), a downstream inactivator of mitogen-activated protein kinase (MAPK) signaling [34–36]. Downregulation of DUSP2 results in a prolonged activation of ERK and p38 MAPK in ectopic endometriotic stromal cells, which explains the increased sensitivity of COX-2 promoter to IL-1β stimulation because it is mediated by ERK- and p38 MAPK-dependent signaling pathway .
In addition to altered COX-2 regulation, PGE2 transporter/carrier may also play important roles on the PGE2 production. Up to date, only few transporters/carriers of PGE2 have been found and are capable of facilitating the uptake or clearance of PGE2 to regulate pericellular PG levels. The co-expression of prostaglandin transporter, preferentially transporting PGE2, and 15-PGDH, metabolizing PGE2 resides in cytoplasm, indeed supporting the idea that uptake of PGE2 is essential for its metabolism . Multidrug resistance-associated protein 4 (MRP4) is one of the few proteins with high specificity to export PGE1 and PGE2 . Interestingly, endometriotic tissue expressed lower 15-PGDH but higher MRP4 mRNA compared to eutopic ones and correlated to higher PGE2production/release [29, 39].
9.4 Actions of PGE2
9.4.1 Control of Steroidogenesis by PGE2
The development and maintenance of endometriosis are highly dependent on estrogen. This notion was supported by several lines of evidences. First, symptoms of endometriosis usually appear after menarche and regress in menopausal or ovariectomized women . Second, a study using the “monkey” animal model also demonstrated that only the group of animals that received capsules with estrogen or progesterone developed endometriosis . During the menstrual cycle, the level of estrogen reaches its maximum before ovulation and maintains at a certain level in the luteal phase. However, after luteolysis and before the production of estrogen by follicles of the next cycle, the estrogen level drops to a minimal level. This raises the question: what is the source of estrogen supporting the survival of endometriotic tissue when the ovarian estrogen is not available? The answers to this question were revealed by multiple studies showing that endometriotic stromal cells actually are capable of producing estrogen. Endometriotic stromal cells not only express proteins/enzymes required for de novo synthesis of estrogen but even express at higher levels compared to its endometrial counterpart. The pro-steroidogenic proteins, including steroidogenic acute regulatory protein (StAR), P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase 17, 20 lyase, aromatase, and 17β-hydroxysteroid dehydrogenase type I, are either aberrantly expressed or elevated in ectopic stromal cells [42–44], whereas the anti-steroidogenic protein, 17β-hydroxysteroid dehydrogenase type II, is suppressed. Among these proteins, StAR and aromatase control two of the most important steps for estrogen production. StAR governs the first step in which hydrophobic cholesterol is carried through the double-membraned mitochondria where the P450 side chain cleavage enzyme resides and aromatase converts androstenedione to estrone.
Expression of StAR in endometriotic stromal cells is induced by PGE2 (Fig. 9.2). This stimulation is unique to endometriotic stromal cells, but not found in eutopic endometrial stromal cells or epithelial cells . PGE2-induced StAR expression is mediated via EP2 receptor . Treatment with PKA inhibitor attenuates PGE2-induced StAR expression, indicating that the EP2 signaling is mediated via typical Gs and PKA/cAMP pathway. In line with this observation, treatment with cell-permeable cAMP also stimulates StAR expression in endometriotic stromal cells. The PKA/cAMP pathway further leads the phosphorylation of cAMP response element-binding protein (CREB), which binds to a CCAAT/enhancer-binding protein (C/EBP) response element in StAR promoter . Phosphorylated CREB recruits CREB-binding protein (CBP), a histone acetyltransferase, causing histone H3 acetylation around StAR promoter and facilitating local nucleosome decondensation, which allows the assembly of transcription complexes . The phosphorylated CREB (15 min), histone H3 acetylation (60 min), and newly transcribed nascent RNA (2 h) were nicely coordinated as the fact that the peak of each molecular event takes place sequentially.
Prostaglandin E2 promotes cell proliferation by two independent EP receptor-mediated pathways. PGE2 binds to EP2 receptor and activates adenylyl cyclase (AC) to generate cyclic AMP (cAMP), which then activates protein kinase A (PKA). Activated PKA translocates to the nucleus to phosphorylate cAMP response element-binding protein (CREB), which binds to StAR (and aromatase) gene promoter. Phosphorylated CREB recruits CREB-binding protein (CBP), a histone acetyl transferase (HAT), to initiate chromatin remodeling and promote StAR and aromatase gene transcription. Upregulation of StAR and aromatase leads to biogenesis of 17-β estradiol (E2) that stimulates fibroblast growth factor-9 (FGF9) production in an autocrine manner. On the other hand, PGE2 binds to EP3 receptor to activate the protein kinase Cδ (PKCδ)-Raf-MEK-ERK signaling pathway that directly results in upregulation of FGF9 transcription. Overexpressed FGF9 then stimulates endometriotic cell proliferation via autocrine and/or paracrine regulations
Along with the aberrant expression of StAR in endometriotic stromal cells, expression of aromatase is also regulated by PGE2 via the EP2 receptor-mediated signaling pathway [47, 48]. Aberrant expression of steroidogenic factor-1 (SF-1) in endometriotic stromal cells alters its sensitivity to PGE2. It has been found that competition between SF-1 and COUP-TFII on the same DNA-binding site in aromatase promoter may contribute to the change of PGE2 sensitivity in endometriotic stromal cells , whereas in endometrial cells, due to the lack of SF-1, COUP-TFII occupies the aromatase promoter, rendering its transcriptional activity. Since the expression of StAR and aromatase is regulated in a similar and parallel aspect, this mechanism enables PGE2 to induce de novo estrogen production from the readily available precursor, cholesterol, without depending on the transport of intermediate metabolites from other organs.
9.4.2 Induction of Peptide Growth Factors by PGE2
Although it is clear that endometriosis is an estrogen-dependent disease, estrogen per se is not a mitogen. The mitogenic effect of estrogen usually is mediated by one or more peptide growth factors. Several well-known peptide growth factors, such as insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and fibroblast growth factor-2 (FGF2), have been shown to exert such estrogen-induced growth effect in other cell types [50–53]. However, evidences that link the expression patterns of these growth factors with the pathogenesis of endometriosis are either inconsistent or even controversial. For example, levels of IGF-1 in peritoneal fluid of women with endometriosis were higher , not different , or even lower  as compared with that in peritoneal fluid of women without endometriosis. The levels of EGF and EGF receptor are not different between ectopic endometriotic lesions and eutopic endometrial tissues [57, 58]. Concentrations of FGF-2 in peritoneal fluid and immunoreactive FGF-2 in pelvic endometriotic cells are not different from those of normal or eutopic counterparts [57, 59, 60].
In contrast to the aforementioned peptide growth factors, FGF9 seems to be a promising candidate that carries estrogen’s mitogenic effect in endometriotic cells. First, expression of FGF9 is induced by estrogen in normal endometrial stromal cells . Second, FGF-9 is consistently expressed by ectopic endometriotic tissue with greater amounts in early stage compared to that in late stage , which correlates with the concentrations of estrogen in the peritoneal fluid of women with endometriosis . Third, expression of FGF9’s high-affinity receptors, including FGFR2IIIb, FGFR2IIIc, FGFR3IIIb, and FGFR3IIIc, is detected in ectopic endometriotic stromal cells . Fourth, FGF9 dose-dependently induces endometrial stromal cell proliferation [61, 63]. Taking these four lines of evidence together with the notion that PGE2 is able to induce estrogen production, it strongly suggests that FGF9 is an estromedin that transmits PGE2’s action in promoting the proliferation of endometriotic cells. Indeed, treatment of endometrial stromal cells with PGE2 dose-dependently induces FGF9 expression, and PGE2-preteated conditioned medium is able to induce stromal cell proliferation, an effect that can be blocked by the addition of anti-FGF9 antibody . Interestingly, it was shown that blocking estrogen signaling by estrogen receptor antagonist, ICI182,780, only partially inhibits PGE2’s action . This observation leads to a new discovery that PGE2 also directly induces FGF9 expression independent of estrogenic effect .
How can PGE2 regulate the same gene expression through two different pathways? To understand this, it is necessary to review the signaling transduction pathways of PGE2. PGE2 regulates various physiological and pathological processes by binding to its receptors on the plasma membrane. In mammals, there are four distinct subtypes of PGE2 receptor, namely EP1, EP2, EP3, and EP4, which are encoded by different genes . All EP receptors are G-protein-coupled receptors. EP2 and EP4 couple to Gs and activate adenylyl cyclase and protein kinase A signaling pathway. Compared to EP2 and EP4, EP1 and EP3 have more complicated pathways. Both EP1 and EP3 have different isoforms generated via alternative splicing varied in their C-terminal cytoplasmic domain, which largely accounts for interaction with G proteins. EP1 has been reported to couple to Gq or Gi/o proteins and promotes the increase of intracellular Ca2+ level and/or inhibition of PKA. EP3 couples to Gs, Gq, or Gi proteins and activates the PKA/PKC/MAPK pathway, immobilization of intracellular Ca2+, or inactivation of PKA . Therefore, different signaling pathway(s) can be regulated by PGE2 dependent on which specific EP was bound . Three EP receptors, EP2, EP3, and EP4, are expressed in human endometrial and endometriotic stromal cells .
The effect of PGE2 on the induction of StAR and aromatase is mediated through binding to the EP2 receptor [45, 47]. In contrast, the induction of FGF9 by PGE2 is mediated by EP3 receptor and its downstream signaling pathway (Fig. 9.2). Treatment with PGE2 or selective EP3 agonist, sulprostone, activates PKCδ, which leads to phosphorylation of ERK. Phosphorylated ERK translocates to the nucleus and activates transcription factor ELK-1, which binds to two response elements residing in the promoter of human FGF9 gene . This direct effect of PGE2 represents the quick response, which occurs between 8 and 12 h after treatment. On the other hand, the PGE2-estrogen-FGF9 axis represents a delayed response, which occurs between 24 and 48 h. Taken together, via two different types of receptors, PGE2 is able to induce the critical survival and proliferating factor, FGF9, to ensure the progression of endometriosis.
9.4.3 Suppression of Phagocytosis by PGE2
One of the most intriguing questions in the pathogenesis of endometriosis is why the immune system fails to clear the retrogradely transported tissues. Normally, apoptotic tissues such as the shed endometrium will be destroyed and engulfed by immune cells. However, in the case of endometriosis, these tissues obviously have some sort of immune privilege that prevent them from being phagocytosed. During the development of endometriosis, the retrograded endometrial tissues induce local inflammation that recruits immune cells, mainly the macrophage, to the peritoneum [66, 67]. Macrophages represent the first line of defense system that either directly phagocytose these aberrantly present cells or activates other immune cells (such as dendritic cells, natural killer cells, and lymphocytes) to launch the antiproliferation responses . However, peritoneal macrophages isolated from patients with endometriosis have greater ability in producing inflammatory agents and poorer capability in phagocytosis [69, 70]. This phenomenon has puzzled researchers for more than three decades. Recently, through a series of investigations, the mechanism of immune deficiency in endometriotic macrophage becomes more and more clear.
The phagocytosis process begins with secreting proteases by activated macrophages. Matrix metalloproteinases (MMPs) are a group of proteases that participate in extracellular matrix degradation . Macrophages can secrete MMP-2, MMP-7, MMP-9, and MMP-12 to degrade elastin and have been implicated to play an important role in the pathogenesis of emphysema and aortic aneurysm [72–75]. In addition, MMP-9 can facilitate the destruction of the type IV collagen-containing basement membrane which separates the epithelial and stromal compartment . This feature makes MMP-9 becoming the prime candidate secreted by macrophages to destroy the retrogradely transported tissues in the peritoneal cavity.
Another important molecule that also contributes to macrophage’s phagocytic function is annexin A2. Annexin A2 has diverse biological functions depending on its cellular localization. When annexin A2 is expressed in membrane-bound form, it promotes the ability of macrophages in remodeling extracellular matrix. Annexin A2 acts as a fibrinolytic receptor that activates plasmin by facilitating the interaction between tissue plasminogen activator and plasminogen . Plasmin serves as a physiological activator which, in turn, converts pro-MMP-9 to active MMP-9. Thus, the activation of membrane annexin A2 will lead to MMP-9 activation. In addition, annexin A2 can be externalized or secreted. Soluble annexin A2 protein activates human monocyte-derived macrophages through toll-like receptor 4 resulting in enhancing phagocytosis . Furthermore, it has been reported that membrane externalization of annexin A2 in macrophages mediates apoptotic cell clearance .
The third line of phagocytic activity involves expression of scavenger receptors on the macrophages to enhance the uptake and degradation of cell debris [80, 81]. Scavenger receptors are a family of structurally diverse receptors having broad ligand specificity that includes low-density lipoprotein, phosphatidylserine, polyanion, and apoptotic cells [82–84]. The known scavenger receptors that participate in phagocytosis of apoptotic cells by macrophages include class A scavenger receptors (SR-AI, SR-AII, SR-AIII)  and class B scavenger receptors (SR-BI, SR-BII, and SR-BIII) [85, 86]. Reduced expression of one of these scavenger receptors may result in loss of phagocytic ability.
By using peritoneal macrophages isolated from individuals with or without endometriosis, we have demonstrated that levels of MMP-9, annexin A2, and SR-BIII (better known as CD36) are all reduced in endometriotic macrophages [87–89] (Fig. 9.3). The decrease in MMP-9, annexin A2, and CD36 is due to exposure to soluble factors in the peritoneal fluid of individuals with endometriosis. Treatment of normal macrophages with peritoneal fluids collected from individuals with endometriosis recaps the phenomenon seen in endometriotic macrophages. In contrast, normal macrophages treated with peritoneal fluids collected from normal individuals are not affected. Interestingly, not only the mRNA and protein levels of MMP-9 are reduced, the MMP-9 enzymatic activity is also inhibited . This markedly impairs macrophage’s ability to digest the basement membrane of retrogradely transported tissues and ultimately contributes to reduced macrophage’s phagocytic ability. Since CD36 is one of the first macrophage receptors to be implicated in the recognition of aged or apoptotic cells [90, 91] and annexin A2 participates in both MMP-9 activation and phagocytosis, reduced expression of CD36 and annexin A2 severely impairs the phagocytic ability of macrophages. Indeed, when CD36 or annexin A2 is knocked down from the normal macrophages, the phagocytic ability is reduced. In contrast, when peritoneal macrophages isolated from individuals with endometriosis are transfected with exogenous CD36 or annexin A2, the phagocytic ability is restored [88, 92].
Prostaglandin E2 inhibits phagocytosis. Under low-PGE2 condition, macrophages are recruited to the peritoneal cavity due to retrogradely transported endometrial tissue-induced inflammation. Recruited macrophages express high levels of annexin A2 (membrane form and soluble form), MMP9, and CD36 to facilitate phagocytosis. Therefore, the retrograded tissues will be engulfed and removed. However, under high concentrations of PGE2 (indicated by red lines), the expression of annexin A2, MMP9, and CD36 is all suppressed. Thus, macrophages lose their phagocytic ability and retrogradely transported endometrial tissues are able to implant and grow in the peritoneum
The next question to ask is which factor in the endometriosis peritoneal fluid exerts such inhibitory effect. Because endometriosis is a chronic inflammatory disease and many proinflammatory cytokines are elevated in the peritoneal fluid of endometriosis [24, 93–96], it is likely that reduced phagocytic ability of peritoneal macrophage is mediated by one or some of these proinflammatory cytokines. Through a series of screens, we identified that PGE2 is the primary factor to inhibit the expression of MMP-9, annexin A2, and CD36 in peritoneal macrophages [88, 89, 92]. PGE2, via binding to the EP2 and EP4 receptors, activates PKA signaling pathway to suppress the expression of MMP-9, annexin A2, and CD36. As expected, treatment of macrophages with PGE2 inhibits phagocytic ability, which can be reversed by adding EP2 receptor antagonist . The in vitro results of PGE2 action in suppressing phagocytosis are further supported by in vivo autologous transplanted mouse model. In this model, uterine endometria from donor mice are peeled off, minced into small pieces, and injected into peritoneal cavity of recipient mice. Recipient mice are treated with or without PGE2 or selective COX-1/COX-2 inhibitors to blunt the biosynthesis of PGE2 for 4 weeks. Mice treated with PGE2 have more endometriotic tissue-like lesions, lower levels of CD36 and annexin A2 in peritoneal macrophages, and reduced phagocytic ability of peritoneal macrophages. In contrast, mice that received selective COX inhibitors develop fewer lesions, express more CD36 and annexin A2 by the peritoneal macrophages, and exert greater phagocytic ability of peritoneal macrophages [88, 92]. Taken altogether, these data reveal that PGE2 utilizes the same receptor-mediated signaling pathway to target three different molecules involved in phagocytosis. Such a safeguarding system to efficiently inhibit macrophage’s phagocytic ability by controlling three target proteins simultaneously is likely due to the evolutional advantage.
9.4.4 Induction of Angiogenesis by PGE2
Establishment of an effective blood supply is a prerequisite for the survival of retrogradely transported endometrial tissues to develop as endometriotic lesions. Newly formed vessels play an indispensible role in the development and progression of endometriosis by providing nutrients, growth factors, and oxygen [97–99]. The newly formed blood vessel can be easily observed on day 4 after the transplantation of mouse endometrium to the peritoneal cavity . Several pro-angiogenic factors that may be involved in blood vessel formation during the development of endometriosis had been reported. Among those, vascular endothelial growth factor (VEGF) and cysteine-rich angiogenic inducer 61 (CYR61) are the most well studied. Concentrations of VEGF in the peritoneal fluid of individuals with endometriosis are greater compared with controls . This VEGF may come from both endometriotic lesions and infiltrated neutrophils and macrophages [27, 97]. Estrogen and COX-2 have been shown to play critical roles in angiogenesis in various tumor models. Both can stimulate VEGF expression and induce endothelial cell proliferation [101–103]. In endometriosis, estrogen has been shown to enhance VEGF production in neutrophils and macrophages  while the expression of COX-2 and VEGF is highly correlated in endometriotic lesions . In vitro study reveals that treatment of endometrial epithelial cells with celecoxib, a selective COX-2 inhibitor, inhibits VEGF expression in comparison to that treated with vehicle . In vivo studies also demonstrate inhibitory effects of selective COX-2 inhibitors in the growth of endometriotic lesion and the development of microvascular networks. Treating rats with rofecoxib induced a decrease in the endometriotic lesion size accompanied by a decrease in peritoneal fluid VEGF levels . Ozawa et al. demonstrate that another selective COX-2 inhibitor, NS398, decreases the size of implants in a xenograft model that implants human ovarian endometrioma to peritonea of SCID mice . Laschke et al. report that the expression of proliferating cell nuclear antigen and VEGF as well as the microvessel density within the endometrial grafts is decreased in NS398-treated golden hamster . Machado et al. also report that parecoxib, also a selective COX-2 inhibitor, reduced lesion size, microvessel density, the number of macrophages, and the expression of VEGF in a rat model of peritoneal endometriosis .
CYR61, a member of the CCN family of growth regulators, is a pro-angiogenic factor that mediates several distinct functions in cell proliferation, adhesion, migration, differentiation, apoptosis, and extracellular matrix production. Cyr61-deficient mice suffer embryonic death due to vascular defects . Expression of CYR61 mRNA is rapidly induced in an immediate early fashion by a spectrum of stimuli such as growth factors, cytokines, and estrogens . The expression of CYR61 in endometrium is elevated in the proliferative phase and menstrual effluents [112, 113]. Aberrant expression of CYR61 has been found in the ectopic lesions of endometriotic women and baboon [35, 114, 115]. The expression of CYR61 is upregulated by PGE2 and hypoxia in human endometrial stromal cells and colon cancer cells, respectively [34, 112]. While PGE2-induced CYR61 is a direct effect, hypoxia-mediated CYR61 may be mediated via downregulation of DUSP2. It has been shown that reduced expression of DUSP2 by hypoxia causes a prolonged phosphorylation of ERK and p38 MAPK, which ultimately leads to upregulation of COX-2 [35, 36]. Therefore, hypoxia-induced CYR61 overexpression is likely also mediated by PGE2.
Taking together all currently available data, it is clear that COX-2-derived PGE2 does play a key role in establishing an effective blood supply system either directly or indirectly during the development of endometriosis. Targeting COX-2-derived PGE2 signaling pathway to blunt new blood vessel formation may be a plausible approach to prevent the development of endometriosis.
9.5 Feed-Forward Loop of PGE2
The consistent production of self-supporting factors is a sophisticated mechanism that keeps endometriotic cells alive despite of the cyclic rises and falls of estrogen and is also the main reason why there is no effective therapeutic regimen for endometriosis. The central piece of this feed-forward self-supporting system is PGE2. There are at least three feed-forward loops to maintain PGE2 at the high concentration in the endometriotic tissues and surrounding local environment (Fig. 9.4). The first positive loop involves estrogen and COX-2. COX-2-derived PGE2 stimulates StAR and aromatase expression in ectopic stromal cells, which leads to aberrant production of estrogen. Autonomous production of estrogen by ectopic tissues induces several known peptide growth factors such as VEGF and FGFs that serve as autocrine (for endometriotic cell) and paracrine (for endothelial cell) factors to stimulate cell proliferation and angiogenesis. On the other hand, estrogen can induce COX-2 expression and thus PGE2 production to form the feed-forward auto-amplification loop .
Positive feed-forward loops of PGE2 actions in endometriosis. Regulation of PGE2 biosynthesis in ectopic endometriotic stromal cells is regulated by predisposition to hypoxic stress, which inhibits expression of dual-specificity phosphatase-2 (DUSP2) and leads to a prolonged activation of ERK. Phosphorylated ERK stabilizes HIF-1α and, at the same time, enhances proinflammatory cytokine-induced COX-2 expression and PGE2 production. These proinflammatory cytokines also induce COX-2 expression and PGE2 production by peritoneal macrophages. Elevated concentration of PGE2stimulates steroidogenesis and angiogenesis to promote cell proliferation and inhibits phagocytosis to prevent ectopic endometriotic tissues from destroyed by macrophages. The effects of PGE2 are augmented by three feed-forward positive regulatory loops: (1) hypoxia-HIF-1α-ERK loop, (2) COX-2-PGE2-estrogen loop, and (3) COX-2-PGE2 proinflammatory cytokine loop. See text for details
The second positive loop requires the cooperation between peritoneal macrophages and endometriotic stromal cells. Peritoneal macrophages secrete proinflammatory cytokines such as IL-1β and PGE2 to induce COX-2 expression in ectopic endometriotic stromal cells and peritoneal macrophages. As a result, more PGE2 is produced. The elevated PGE2 not only induces more COX-2 expression by macrophages but also inhibits phagocytosis. Attenuated phagocytic ability of macrophages enables ectopic endometriotic tissues to grow and produce more PGE2 upon stimulation by proinflammatory cytokines or estrogen.
The third positive loop, to some extent, may be the most important one to initiate the whole pathological process of endometriosis. It starts with the increase of hypoxic stress due to lack of blood supply to the endometrium right before the onset of menstruation. Increased hypoxic stress causes the accumulation of HIF-1α, which then translocates to the nucleus and dimerizes with HIF-1β to regulate gene expression. Hypoxia-mediated downregulation of DUSP2 causes a prolonged activation of ERK and p38 MAPK, which results in increased sensitivity of COX-2 gene to proinflammatory cytokine stimulation. As a result, the endometriotic lesions are more vulnerable to exogenous stimulation and produce more PGE2. Moreover, the activation of ERK enhances nuclear accumulation of HIF-1α , which further suppresses DUSP2 and thus enhances ERK activation. This may explain why HIF-1α protein  and phosphorylated ERK  are elevated in ectopic endometriotic lesions. Because ERK and p38 MAPK signaling controls many endometrial functions such as IL-1β and macrophage migration inhibitory factor-induced COX-2 expression [25, 119, 120], macrophage migration inhibitory factor-stimulated production of angiogenic factors , basal endometrial cells survival , and estrogen-stimulated cell proliferation , downregulation of DUSP2 in ectopic endometriotic cells points out the importance of hypoxia and/or HIF-1α in the pathogenesis of endometriosis.
As we can see in Fig. 9.4, these three positive feed-forward loops are not separated but rather interlinked to form a very complicated auto-amplification gene regulatory network. It involves multiple genes and environmental factors. Thus, how to disrupt these tightly regulated, self-supporting feed-forward loops represents a great challenge in treating endometriosis.
9.6 Targeting PGE2 Signaling Pathway as a Potential Therapeutic Approach
As reviewed above, PGE2 exerts multiple pathological functions to regulate the development of endometriosis and minimize or eradicate those effects triggered by PGE2 and represents a plausible approach to prevent or cure endometriosis. Inhibiting the production of PGE2 by ectopic endometriotic stromal cells and by peritoneal macrophages might be an option. However, given the short half-life of COX inhibitors and the unfavorable side effects caused by long-term use of NSAIDs, suppressing PGE2 production to cure endometriosis may not be an ideal choice. An alternative approach is to block the downstream signaling pathways to terminate PGE2’s action. For example, it has been shown recently that blocking EP2/EP4 may prevent PGE2 to transactivate EGF receptor and induce apoptosis in SV40-immortalized endometriotic stromal and epithelial cells. Similar approach may be applicable to block EP3 receptor on endometriotic stromal cells to inhibit the production of FGF-9 or to target EP2 on macrophages to prevent suppression of phagocytic ability by PGE2. In addition, inhibition of multiple enzymes to disrupt the positive feedback loops of PGE2 overproduction may be an alternative. Indeed, dienogest, a synthetic progestin that inhibits COX-2 and aromatase activities, was found to be effective in ameliorating endometriotic symptoms [123–125]. In light of this recent finding, developing effective small molecules to terminate PGE2-mediated signaling is more likely a promising therapeutic strategy to treat endometriosis.
This work was supported by grants from National Science Council of Taiwan (NSC-101-2320-B-006-030-MY3 to SJT and NSC-101-2314-B-006-043-MY2 to MHW). KYH wrote the first draft and proof-read the final manuscript. MHW and SJT edited and wrote the final draft. SJT designed and supervised the project. All authors read and approved the final draft.
Gruenwald P. Origin of endometriosis from the mesenchyme of the coelomic walls. Am J Obstet Gynecol. 1942;44:474.
Olive DL, Schwartz LB. Endometriosis. N Engl J Med. 1993;328:1759–69.PubMed
Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3(93–110):43.PubMed
Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–69.
von Recklinghausen F. Adenomyomas and cystadenomas of the wall of the uterus and tube: their origin as remnants of the wolffian body. Wien Klin Wochenschr. 1986;8:530.
Nunley Jr WC, Kitchin 3rd JD. Congenital atresia of the uterine cervix with pelvic endometriosis. Arch Surg. 1980;115:757–8.PubMed
Olive DL, Henderson DY. Endometriosis and mullerian anomalies. Obstet Gynecol. 1987;69:412–5.PubMed
Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986;154:39–43.PubMed
D’Hooghe TM. Clinical relevance of the baboon as a model for the study of endometriosis. Fertil Steril. 1997;68:613–25.PubMed
D’Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update. 2002;8:84–8.PubMed
Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64:151–4.PubMed
Chen C, Bazan NG. Lipid signaling: sleep, synaptic plasticity, and neuroprotection. Prostaglandins Other Lipid Mediat. 2005;77:65–76.PubMed
Huang ZL, Sato Y, Mochizuki T, Okada T, Qu WM, Yamatodani A, Urade Y, Hayaishi O. Prostaglandin E2 activates the histaminergic system via the EP4 receptor to induce wakefulness in rats. J Neurosci. 2003;23:5975–83.PubMed
Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol. 2012;188:21–8.PubMedCentralPubMed
Pelus LM, Hoggatt J. Pleiotropic effects of prostaglandin E2 in hematopoiesis; prostaglandin E2 and other eicosanoids regulate hematopoietic stem and progenitor cell function. Prostaglandins Other Lipid Mediat. 2011;96:3–9.PubMedCentralPubMed
Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem. 2007;282:11613–7.PubMed
Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M, Ueno A, Oh S, Kudo I. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem. 2000;275:32783–92.PubMed
Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K. Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. Biochem Biophys Res Commun. 2002;291:884–9.PubMed
Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo I. Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem. 2000;275:32775–82.PubMed
Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T, Ohmiya Y, Watanabe K, Kudo I. Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and −2. J Biol Chem. 2003;278:37937–47.PubMed
Badawy SZ, Marshall L, Cuenca V. Peritoneal fluid prostaglandins in various stages of the menstrual cycle: role in infertile patients with endometriosis. Int J Fertil. 1985;30:48–52.PubMed
Chishima F, Hayakawa S, Sugita K, Kinukawa N, Aleemuzzaman S, Nemoto N, Yamamoto T, Honda M. Increased expression of cyclooxygenase-2 in local lesions of endometriosis patients. Am J Reprod Immunol. 2002;48:50–6.PubMed
Ota H, Igarashi S, Sasaki M, Tanaka T. Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. Hum Reprod. 2001;16:561–6.PubMed
Wu MH, Sun HS, Lin CC, Hsiao KY, Chuang PC, Pan HA, Tsai SJ. Distinct mechanisms regulate cyclooxygenase-1 and −2 in peritoneal macrophages of women with and without endometriosis. Mol Hum Reprod. 2002;8:1103–10.PubMed
Wu MH, Wang CA, Lin CC, Chen LC, Chang WC, Tsai SJ. Distinct regulation of cyclooxygenase-2 by interleukin-1beta in normal and endometriotic stromal cells. J Clin Endocrinol Metab. 2005;90:286–95.PubMed
Karck U, Reister F, Schafer W, Zahradnik HP, Breckwoldt M. PGE2 and PGF2 alpha release by human peritoneal macrophages in endometriosis. Prostaglandins. 1996;51:49–60.PubMed
Lin YJ, Lai MD, Lei HY, Wing LY. Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology. 2006;147:1278–86.PubMed
Gupta S, Agarwal A, Sekhon L, Krajcir N, Cocuzza M, Falcone T. Serum and peritoneal abnormalities in endometriosis: potential use as diagnostic markers. Minerva Ginecol. 2006;58:527–51.PubMed
Lousse JC, Defrere S, Colette S, Van Langendonckt A, Donnez J. Expression of eicosanoid biosynthetic and catabolic enzymes in peritoneal endometriosis. Hum Reprod. 2010;25:734–41.PubMed
Sano M, Morishita T, Nozaki M, Yokoyama M, Watanabe Y, Nakano H. Elevation of the phospholipase A2 activity in peritoneal fluid cells from women with endometriosis. Fertil Steril. 1994;61:657–62.PubMed
Chishima F, Hayakawa S, Yamamoto T, Sugitani M, Karasaki-Suzuki M, Sugita K, Nemoto N. Expression of inducible microsomal prostaglandin E synthase in local lesions of endometriosis patients. Am J Reprod Immunol. 2007;57:218–26.PubMed
Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. 2007;2007:cm8.PubMed
Wu MH, Chen KF, Lin SC, Lgu CW, Tsai SJ. Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1alpha. Am J Pathol. 2007;170:590–8.PubMedCentralPubMed
Lin SC, Chien CW, Lee JC, Yeh YC, Hsu KF, Lai YY, Lin SC, Tsai SJ. Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest. 2011;121:1905–16.PubMedCentralPubMed
Lin SC, Wang CC, Wu MH, Yang SH, Li YH, Tsai SJ. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J Clin Endocrinol Metab. 2012;97:E1515–23.PubMed
Wu MH, Lin SC, Hsiao KY, Tsai SJ. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. J Pathol. 2011;225:390–400.PubMed
Nomura T, Lu R, Pucci ML, Schuster VL. The two-step model of prostaglandin signal termination: in vitro reconstitution with the prostaglandin transporter and prostaglandin 15 dehydrogenase. Mol Pharmacol. 2004;65:973–8.PubMed
Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003;100:9244–9.PubMedCentralPubMed
Gori I, Rodriguez Y, Pellegrini C, Achtari C, Hornung D, Chardonnens E, Wunder D, Fiche M, Canny GO. Augmented epithelial multidrug resistance-associated protein 4 expression in peritoneal endometriosis: regulation by lipoxin A. Fertil Steril. 2013;99:1965.PubMed
Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willett WC, Hunter DJ. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol. 2004;104:965–74.PubMed
Dizerega GS, Barber DL, Hodgen GD. Endometriosis: role of ovarian steroids in initiation, maintenance, and suppression. Fertil Steril. 1980;33:649–53.PubMed
Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, Gurates B, Attar R, Yaegashi N, Hales DB, Bulun SE. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009;94:623–31.PubMedCentralPubMed
Noble LS, Simpson ER, Johns A, Bulun SE. Aromatase expression in endometriosis. J Clin Endocrinol Metab. 1996;81:174–9.PubMed
Tsai SJ, Wu MH, Lin CC, Sun HS, Chen SM. Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J Clin Endocrinol Metab. 2001;86:5765–73.PubMed
Sun HS, Hsiao KY, Hsu CC, Wu MH, Tsai SJ. Transactivation of steroidogenic acute regulatory protein in human endometriotic stromal cells is mediated by the prostaglandin EP2 receptor. Endocrinology. 2003;144:3934–42.PubMed
Hsu CC, Lu CW, Huang BM, Wu MH, Tsai SJ. Cyclic adenosine 3′,5′-monophosphate response element-binding protein and CCAAT/enhancer-binding protein mediate prostaglandin E2-induced steroidogenic acute regulatory protein expression in endometriotic stromal cells. Am J Pathol. 2008;173:433–41.PubMedCentralPubMed
Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE. Prostaglandin E2 stimulates aromatase expression in endometriosis- derived stromal cells. J Clin Endocrinol Metab. 1997;82:600–6.PubMed
Zeitoun K, Takayama K, Michael MD, Bulun SE. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element. Mol Endocrinol. 1999;13:239–53.PubMed
Zeitoun KM, Bulun SE. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril. 1999;72:961–9.PubMed
Cooke PS, Buchanan DL, Lubahn DB, Cunha GR. Mechanism of estrogen action: Lesions from the estradiol receptor-α knockout mouse. Biol Reprod. 1998;59:470–5.PubMed
Croze F, Kennedy TG, Schroedter IC, Friesen HG, Murphy LJ. Expression of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in the rat uterus during decidualization. Endocrinology. 1990;127:1995–2000.PubMed
Haining RE, Cameron IT, van Papendorp C, Davenport AP, Prentice A, Thomas EJ, Smith SK. Epidermal growth factor in human endometrium: proliferative effects in culture and immunocytochemical localization in normal and endometriotic tissues. Hum Reprod. 1991;6:1200–5.PubMed
Pierro E, Minici F, Alesiani O, Miceli F, Proto C, Screpanti I, Mancuso S, Lanzone A. Stromal-epithelial interactions modulate estrogen responsiveness in normal human endometrium. Biol Reprod. 2001;64:831–8.PubMed
Kim JG, Suh CS, Kim SH, Choi YM, Moon SY, Lee JY. Insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP-3 protease activity in the peritoneal fluid of patients with and without endometriosis. Fertil Steril. 2000;73:996–1000.PubMed
Matalliotakis IM, Goumenou AG, Koumantakis GE, Neonaki MA, Koumantakis EE, Dionyssopoulou E, Athanassakis I, Vassiliadis S. Serum concentrations of growth factors in women with and without endometriosis: the action of anti-endometriosis medicines. Int Immunopharmacol. 2003;3:81–9.PubMed
Sbracia M, Zupi E, Alo P, Manna C, Marconi D, Scarpellini F, Grasso JA, Di Tondo U, Romanini C. Differential expression of IGF-I and IGF-II in eutopic and ectopic endometria of women with endometriosis and in women without endometriosis. Am J Reprod Immunol. 1997;37:326–9.PubMed
Huang JC, Papasakelariou C, Dawood MY. Epidermal growth factor and basic fibroblast growth factor in peritoneal fluid of women with endometriosis. Fertil Steril. 1996;65:931–4.PubMed
Huang JC, Yeh J. Quantitative analysis of epidermal growth factor receptor gene expression in endometriosis. J Clin Endocrinol Metab. 1994;79:1097–101.PubMed
Ferriani RA, Charnock-Jones DS, Prentice A, Thomas EJ, Smith SK. Immunohistochemical localization of acidic and basic fibroblast growth factors in normal human endometrium and endometriosis and the detection of their mRNA by polymerase chain reaction. Hum Reprod. 1993;8:11–6.PubMed
Seli E, Zeyneloglu HB, Senturk LM, Bahtiyar OM, Olive DL, Arici A. Basic fibroblast growth factor: peritoneal and follicular fluid levels and its effect on early embryonic development. Fertil Steril. 1998;69:1145–8.PubMed
Tsai SJ, Wu MH, Chen HM, Chuang PC, Wing LY. Fibroblast growth factor-9 is an endometrial stromal growth factor. Endocrinology. 2002;143:2715–21.PubMed
Wing L-YC, Chuang P-C, Wu M-H, Chen H-M, Tsai S-J. Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen. J Clin Endocrinol Metab. 2003;88:5547–54.PubMed
Wing LY, Chen HM, Chuang PC, Wu MH, Tsai SJ. The mammalian target of rapamycin-p70 ribosomal S6 kinase but not phosphatidylinositol 3-kinase-Akt signaling is responsible for fibroblast growth factor-9-induced cell proliferation. J Biol Chem. 2005;280:19937–47.PubMed
Chuang PC, Sun HS, Chen TM, Tsai SJ. Prostaglandin E2 induces fibroblast growth factor 9 via EP3-dependent protein kinase Cdelta and Elk-1 signaling. Mol Cell Biol. 2006;26:8281–92.PubMedCentralPubMed
Breyer RM, Bagdassarian CK, Myers SA, Breyer MD. Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol. 2001;41:661–90.PubMed
Dunselman GA, Hendrix MG, Bouckaert PX, Evers JL. Functional aspects of peritoneal macrophages in endometriosis of women. J Reprod Fertil. 1988;82:707–10.PubMed
Haney AF, Muscato JJ, Weinberg JB. Peritoneal fluid cell populations in infertility patients. Fertil Steril. 1981;35:696–8.PubMed
Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.PubMed
Dmowski WP, Gebel H, Braun DP. Decreased apoptosis and sensitivity to macrophage mediated cytolysis of endometrial cells in endometriosis. Hum Reprod Update. 1998;4:696–701.PubMed
Steele RW, Dmowski WP, Marmer DJ. Immunologic aspects of human endometriosis. Am J Reprod Immunol. 1984;6:33–6.PubMed
Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39.PubMed
Campbell EJ, Cury JD, Shapiro SD, Goldberg GI, Welgus HG. Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases, and tissue inhibitor of metalloproteinases. J Immunol. 1991;146:1286–93.PubMed
Curci JA, Liao S, Huffman MD, Shapiro SD, Thompson RW. Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J Clin Invest. 1998;102:1900–10.PubMedCentralPubMed
Dhami R, Gilks B, Xie C, Zay K, Wright JL, Churg A. Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by alpha1-antitrypsin. Am J Respir Cell Mol Biol. 2000;22:244–52.PubMed
Welgus HG, Campbell EJ, Cury JD, Eisen AZ, Senior RM, Wilhelm SM, Goldberg GI. Neutral metalloproteinases produced by human mononuclear phagocytes. Enzyme profile, regulation, and expression during cellular development. J Clin Invest. 1990;86:1496–502.PubMedCentralPubMed
McMillan JI, Weeks R, West JW, Bursten S, Rice GC, Lovett DH. Pharmacological inhibition of gelatinase B induction and tumor cell invasion. Int J Cancer. 1996;67:523–31.PubMed
Brownstein C, Deora AB, Jacovina AT, Weintraub R, Gertler M, Khan KM, Falcone DJ, Hajjar KA. Annexin II mediates plasminogen-dependent matrix invasion by human monocytes: enhanced expression by macrophages. Blood. 2004;103:317–24.PubMed
Swisher JF, Burton N, Bacot SM, Vogel SN, Feldman GM. Annexin A2 tetramer activates human and murine macrophages through TLR4. Blood. 2010;115:549–58.PubMedCentralPubMed
Fan X, Krahling S, Smith D, Williamson P, Schlegel RA. Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes. Mol Biol Cell. 2004;15:2863–72.PubMedCentralPubMed
Febbraio M, Hajjar DP, Silverstein RL. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest. 2001;108:785–91.PubMedCentralPubMed
Linton MF, Fazio S. Class A scavenger receptors, macrophages, and atherosclerosis. Curr Opin Lipidol. 2001;12:489–95.PubMed
Krieger M, Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–37.PubMed
Platt N, da Silva RP, Gordon S. Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol. 1998;8:365–72.PubMed
Rigotti A, Acton SL, Krieger M. The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids. J Biol Chem. 1995;270:16221–4.PubMed
Savill J, Dransfield I, Hogg N, Haslett C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature. 1990;343:170–3.PubMed
Savill J, Hogg N, Ren Y, Haslett C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest. 1992;90:1513–22.PubMedCentralPubMed
Chuang PC, Wu MH, Shoji Y, Tsai SJ. Downregulation of CD36 results in reduced phagocytic ability of peritoneal macrophages of women with endometriosis. J Pathol. 2009;219:232–41.PubMed
Wu MH, Chuang PC, Lin YJ, Tsai SJ. Suppression of annexin A2 by prostaglandin E(2) impairs phagocytic ability of peritoneal macrophages in women with endometriosis. Hum Reprod. 2013;28:1045–53.PubMed
Wu MH, Shoji Y, Wu MC, Chuang PC, Lin CC, Huang MF, Tsai SJ. Suppression of matrix metalloproteinase-9 by prostaglandin E(2) in peritoneal macrophage is associated with severity of endometriosis. Am J Pathol. 2005;167:1061–9.PubMedCentralPubMed
Navazo MD, Daviet L, Savill J, Ren Y, Leung LL, McGregor JL. Identification of a domain (155–183) on CD36 implicated in the phagocytosis of apoptotic neutrophils. J Biol Chem. 1996;271:15381–5.PubMed
Trial J, Rice L. Erythropoietin withdrawal leads to the destruction of young red cells at the endothelial-macrophage interface. Curr Pharm Des. 2004;10:183–90.PubMed
Chuang PC, Lin YJ, Wu MH, Wing LY, Shoji Y, Tsai SJ. Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. Am J Pathol. 2010;176:850–60.PubMedCentralPubMed
Harada T, Yoshioka H, Yoshida S, Iwabe T, Onohara Y, Tanikawa M, Terakawa N. Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am J Obstet Gynecol. 1997;176:593–7.PubMed
Iwabe T, Harada T, Tsudo T, Tanikawa M, Onohara Y, Terakawa N. Pathogenetic significance of increased levels of interleukin-8 in the peritoneal fluid of patients with endometriosis. Fertil Steril. 1998;69:924–30.PubMed
Koyama N, Matsuura K, Okamura H. Cytokines in the peritoneal fluid of patients with endometriosis. Int J Gynaecol Obstet. 1993;43:45–50.PubMed
Kupker W, Schultze-Mosgau A, Diedrich K. Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update. 1998;4:719–23.PubMed
Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 1998;13:1686–90.PubMed
Groothuis PG, Nap AW, Winterhager E, Grummer R. Vascular development in endometriosis. Angiogenesis. 2005;8:147–56.PubMed
Taylor RN, Lebovic DI, Mueller MD. Angiogenic factors in endometriosis. Ann N Y Acad Sci. 2002;955:89–100. discussion 18, 396–406.PubMed
Mahnke JL, Dawood MY, Huang JC. Vascular endothelial growth factor and interleukin-6 in peritoneal fluid of women with endometriosis. Fertil Steril. 2000;73:166–70.PubMed
Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, Tarnawski AS. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med. 1999;5:1418–23.PubMed
Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;93:705–16.PubMed
Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest. 2000;105:1589–94.PubMedCentralPubMed
Ceyhan ST, Onguru O, Baser I, Gunhan O. Expression of cyclooxygenase-2 and vascular endothelial growth factor in ovarian endometriotic cysts and their relationship with angiogenesis. Fertil Steril. 2008;90:988–93.PubMed
Olivares C, Bilotas M, Buquet R, Borghi M, Sueldo C, Tesone M, Meresman G. Effects of a selective cyclooxygenase-2 inhibitor on endometrial epithelial cells from patients with endometriosis. Hum Reprod. 2008;23:2701–8.PubMed
Dogan E, Saygili U, Posaci C, Tuna B, Caliskan S, Altunyurt S, Saatli B. Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril. 2004;82 Suppl 3:1115–20.PubMed
Ozawa Y, Murakami T, Tamura M, Terada Y, Yaegashi N, Okamura K. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via antiangiogenic activity in severe combined immunodeficiency mice. Fertil Steril. 2006;86:1146–51.PubMed
Laschke MW, Elitzsch A, Scheuer C, Vollmar B, Menger MD. Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis. Fertil Steril. 2007;87:163–71.PubMed
Machado DE, Berardo PT, Landgraf RG, Fernandes PD, Palmero C, Alves LM, Abrao MS, Nasciutti LE. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis with an antiangiogenic effect in a rat model. Fertil Steril. 2010;93:2674–9.PubMed
Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF. CYR61 (CCN1) is essential for placental development and vascular integrity. Mol Cell Biol. 2002;22:8709–20.PubMedCentralPubMed
Chen Y, Du XY. Functional properties and intracellular signaling of CCN1/Cyr61. J Cell Biochem. 2007;100:1337–45.PubMed
Gashaw I, Stiller S, Boing C, Kimmig R, Winterhager E. Premenstrual regulation of the pro-angiogenic factor CYR61 in human endometrium. Endocrinology. 2008;149:2261–9.PubMed
MacLaughlan SD, Palomino WA, Mo B, Lewis TD, Lininger RA, Lessey BA. Endometrial expression of Cyr61: a marker of estrogenic activity in normal and abnormal endometrium. Obstet Gynecol. 2007;110:146–54.PubMed
Absenger Y, Hess-Stumpp H, Kreft B, Kratzschmar J, Haendler B, Schutze N, Regidor PA, Winterhager E. Cyr61, a deregulated gene in endometriosis. Mol Hum Reprod. 2004;10:399–407.PubMed
Gashaw I, Hastings JM, Jackson KS, Winterhager E, Fazleabas AT. Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol Reprod. 2006;74:1060–6.PubMed
Attar E, Bulun SE. Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum Reprod Update. 2006;12:49–56.PubMed
Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem. 1999;274:32631–7.PubMed
Murk W, Atabekoglu CS, Cakmak H, Heper A, Ensari A, Kayisli UA, Arici A. Extracellularly signal-regulated kinase activity in the human endometrium: possible roles in the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2008;93:3532–40.PubMed
Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A. Up-regulation of cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells by macrophage migration inhibitory factor: involvement of novel kinase signaling pathways. Endocrinology. 2009;150:3128–37.PubMedCentralPubMed
Tamura M, Sebastian S, Yang S, Gurates B, Fang Z, Bulun SE. Interleukin-1beta elevates cyclooxygenase-2 protein level and enzyme activity via increasing its mRNA stability in human endometrial stromal cells: an effect mediated by extracellularly regulated kinases 1 and 2. J Clin Endocrinol Metab. 2002;87:3263–73.PubMed
Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A. Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways. J Clin Endocrinol Metab. 2010;95:E403–12.PubMed
Ngo C, Nicco C, Leconte M, Chereau C, Arkwright S, Vacher-Lavenu MC, Weill B, Chapron C, Batteux F. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J Pathol. 2010;222:148–57.PubMed
Momoeda M, Harada T, Terakawa N, Aso T, Fukunaga M, Hagino H, Taketani Y. Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res. 2009;35:1069–76.PubMed
Shimizu Y, Mita S, Takeuchi T, Notsu T, Mizuguchi K, Kyo S. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids. 2010;76:60–7.PubMed
Yamanaka K, Xu B, Suganuma I, Kusuki I, Mita S, Shimizu Y, Mizuguchi K, Kitawaki J. Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E(2) production in human endometriotic stromal cells in spheroid culture. Fertil Steril. 2012;97:477–82.PubMed