Whether the EP4 receptor-induced IL-8 release from endothelial cells actually results in neutrophil recruitment to the tissue has not yet been addressed, but similar EP4 receptor-mediated expression of proinflammatory cytokines was observed in airway and colon epithelial cell lines (Dey et al., 2009; T. Li et al., 2011). Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. Okano M., Sugata Y., Fujiwara T., Matsumoto R., Nishibori M., Shimizu K. E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2. An EP4 receptor antagonist as well EP4 Gene knockdown inhibit the in vitro proliferation and invasiveness of human breast cancer cells. The structure of the prostaglandin EP4 receptor gene and related pseudogenes. Bethesda, MD 20894, Web Policies The activation of this signaling cascade has been proposed to regulate the migration and metastasis of colorectal carcinomas (Fig. Nakagawa N., Yuhki K., Kawabe J., Fujino T., Takahata O., Kabara M. The intrinsic prostaglandin E2EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice. Before Tumor location and disease stage determine the need for neoadjuvant chemotherapy. EP4 receptor activation in a murine model of Alzheimer's disease, EP4 deficiency or the EP4 antagonist ONO-AE3-208 decreased amyloid- levels in the brain and improved the behavioral performance of the animals (Hoshino et al., 2012). Role of prostaglandin E2 in tissue repair and regeneration - PMC 8600 Rockville Pike Billot X., Chateauneuf A., Chauret N., Denis D., Greig G., Mathieu M.C. Further increasing the complexity of EP4 receptor signaling, a binding site for EPRAP has been identified on the long cytoplasmic tail of EP4 in human macrophages (Takayama et al., 2006). Xie C., Liang B., Xue M., Lin A.S., Loiselle A., Schwarz E.M. Subscribe. Park G.Y., Christman J.W. However, the EP receptor mediating the protective role of PGE2 in sepsis has not yet been identified, but it is likely that EP4 receptor-mediated suppression of monocyte cytokine release plays a major role (Iwasaki et al., 2003). government site. Ohshiba T., Miyaura C., Ito A. Nishitani K., Ito H., Hiramitsu T., Tsutsumi R., Tanida S., Kitaori T. PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes. Araki H., Ukawa H., Sugawa Y., Yagi K., Suzuki K., Takeuchi K. The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach. Shio H., Ramwell P.W., Jessup S.J. Prostanoids are derived from arachidonic acid, a 20 carbon polyunsaturated fatty acid, which is usually found in phosphoglycerides of mammalian cell membranes (Fig. However, this anti-inflammatory response to PGE2 was not mediated by the cAMP/PKA/CREB pathway. An additional EP4 receptor signaling molecule independent of PKA is Epac, i.e. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. Fujino H., West K.A., Regan J.W. Aso H., Ito S., Mori A., Suganuma N., Morioka M., Takahara N. Differential regulation of airway smooth muscle cell migration by e-prostanoid receptor subtypes. A conserved threonine in the second extracellular loop of the human EP2 and EP4 receptors is required for ligand binding. Morteau O., Morham S.G., Sellon R., Dieleman L.A., Langenbach R., Smithies O. Disruption of the intestinal mucosal barrier is characteristic in several gastrointestinal diseases including ischemiareperfusion, inflammatory bowel disease and NSAID-induced gastropathy (DeMeo et al., 2002). Arachidonic acid is liberated from membrane phospholipids by phospholipase A2 enzyme activity. Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the central nervous system. However, changes in EP4 expression during adenoma to carcinoma progression have not been investigated, neither has whether levels of EP4 influence important markers of . 3). Author Contributions: . 14q22.1), contains 2 introns and 3 exons, and codes for a G protein coupled receptor . Murn J., Alibert O., Wu N., Tendil S., Gidrol X. Prostaglandin E2 regulates B cell proliferation through a candidate tumor suppressor, Ptger4. Prostaglandin E2 (PGE2) is a lipid mediator that modulates the function of myeloid immune cells such as macrophages and dendritic cells (DCs) through the activation of the G protein-coupled receptors EP2 and EP4. In clinical practice, COX inhibitors are being used to control ectopic bone formation, but their use in the treatment of fracture pain has raised concern with respect to a potential delay of fracture healing (Vuolteenaho et al., 2008). Tables13 provide an overview of currently described selective and non-selective agonists, and antagonists for EP4, respectively, and their affinity, dosing and biological effects. As such, the EP4 receptor and EPRAP might provide novel therapeutic targets in chronic inflammatory diseases with excess of macrophage activation, such as atherosclerosis and sepsis. Prostanoid stimulation of anion secretion in guinea-pig gastric and ileal mucosa is mediated by different receptors. Kunikata T., Araki H., Takeeda M., Kato S., Takeuchi K. Prostaglandin E prevents indomethacin-induced gastric and intestinal damage through different EP receptor subtypes. An important prerequisite of cardiovascular homeostasis is tight regulation of platelet aggregation. Anatomical profiling of G protein-coupled receptor expression. Sugimoto Y., Narumiya S. Prostaglandin E receptors. Prijatelj M., Celhar T., Gobec M., Mlinaric-Rascan I. EP4 receptor signalling in immature B cells involves cAMP and NF-kappaB dependent pathways. Smith J.P., Haddad E.V., Downey J.D., Breyer R.M., Boutaud O. PGE(2) decreases reactivity of human platelets by activating EP2 and EP4. Finally, EP4 receptors in podocytes signal to induce COX-2 through an indirectly cAMP-dependent, PKA-independent signaling pathway: AMP-activated protein kinase (AMPK) (Faour et al., 2008). Role of PGE-type receptor 4 in auditory function and noise-induced hearing loss in mice. A potential role of EP4 receptors in metabolic disease is further supported by enhanced adipogenesis from mouse embryonic fibroblasts of EP4-deficient mice and by the inhibitory effect of PGE2 acting via EP4 receptors and peroxisome proliferator-activated receptor- (Inazumi et al., 2011). COX-2 inhibitors and cardiovascular risk. EP4 receptor activation in endothelial cells caused intracellular cAMP formation. B cell receptor activation upregulates EP4 receptors on immature B cells and promotes their apoptosis (Prijatelj et al., 2011). EP4 receptor Golgi apparatus Plasma membrane Growth cones 1. Medical progress: the pathophysiology and treatment of sepsis. PDF Different effects of EP2 and EP4 receptors in TGF1 induced mesangial El-Nefiawy N., Abdel-Hakim K., Kanayama N. The selective prostaglandin EP4 agonist, APS-999 Na, induces follicular growth and maturation in the rat ovary. EP4 cytoplasmic staining did not correlate with OS (0-1 vs. 2+, 23.8 vs. 28.8 mo; HR = 1.2, p = 0.81). Philipose S., Ofner M., Heinemann A., Schuligoi R. Prostaglandin E2 acts via the EP4 receptor to inhibit platelet aggregation. Epigenetic deregulation of the COX pathway in cancer. [6][15][19][13], EP4 receptors are highly expressed in the small intestine and colon. EP4 receptor-mediated protection in a cerebral ischemia mouse model was found to depend on the Akt/eNOS pathway (Liang et al., 2011). Similar to its gastrointestinal effects, lubiprostone was shown to stimulate tracheal submucosal gland secretion in pigs, sheep and humans without producing bronchoconstriction (Joo et al., 2009). Honda A., Sugimoto Y., Namba T., Watabe A., Irie A., Negishi M. Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 subtype. However, conjunctival hyperemia and corneal neovascularization were also observed (Aguirre et al., 2009). EP 4 prostanoid receptor coupling to a pertussis toxin-sensitive inhibitory G protein. McCoy J.M., Wicks J.R., Audoly L.P. Bioinformatics Unmasks the Maneuverers of Pain Pathways in Acute Kidney Philipose S., Konya V., Sreckovic I., Marsche G., Lippe I.T., Peskar B.A. Lack of EP4 receptors on bone marrow-derived cells enhances inflammation in atherosclerotic lesions. the location research, EP4 is positioned in both glomerulus and peritubular capillar y. Crucial involvement of the EP4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide. Murase A., Taniguchi Y., Tonai-Kachi H., Nakao K., Takada J. Lubiprostone targets prostanoid signaling and promotes ion transporter trafficking, mucus exocytosis, and contractility. EP2 and EP4 agonists stimulated the production of VEGF in the spiral ganglion suggesting a beneficial effect in diseases like acute sensorineural hearing loss (Hori et al., 2010). EP4 protein is found in humans as measured by immunochemistry in pulmonary veins; kidney glomeruli and Tunica media of kidney arteries; corpus cavernosum of the penis; carotid artery atherosclerotic plaques; Abdominal aorta aneurysms; corneal endothelium, corneal keratocytes, trabecular cells, ciliary epithelium, conjunctival stromal cells, and iridal stromal cells of the eye; and gingival fibroblasts. Fujino H., Regan J.W. GeneRIFs: Gene References Into Functions PARP14 regulates EP4 receptor expression in human colon cancer HCA-7 cells. Desai S., April H., Nwaneshiudu C., Ashby B. Fabre J.E., Nguyen M., Athirakul K., Coggins K., McNeish J.D., Austin S. Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. antigen-presenting cells located primarily in the skin and mucus membranes) to mature, migrate, and direct the early stage of immune responses; c) inhibit antibody-producing B cells from proliferating; d) suppresses the development of Atherosclerosis plaques by promoting the death (i.e. Cebola I., Peinado M.A. Ohinata K., Suetsugu K., Fujiwara Y., Yoshikawa M. Activation of prostaglandin E receptor EP4 subtype suppresses food intake in mice. Abstract. Other types of cancer that might be sensitive to EP4 receptor stimulation include mycosis fungoides (Kopp et al., 2010), pancreatic adenocarcinoma (Funahashi et al., 2008), esophageal adenocarcinoma (Ogunwobi et al., 2006; Jimenez et al., 2010), endometrium cancer (Catalano et al., 2011), prostate cancer (Terada et al., 2010; Miao et al., 2012), neuroblastoma (Rasmuson et al., 2012), and glioblastoma (Kambe et al., 2009). EP4 receptors are the most widely expressed PGE2 receptors in the body, and research over the past ten years or so has unraveled that numerous novel, or well-recognized biological effects of PGE2 can be attributed to EP4 receptor activation (Fig. EP4 antagonists inhibit metastasis in preclinical models. Luft T., Jefford M., Luetjens P., Toy T., Hochrein H., Masterman K.A. Additionally, EP4 receptor-overexpressing CHO cells showed rapid desensitization and internalization of EP4 after PGE2 stimulation, which was not observed with EP2 receptors (Nishigaki et al., 1996). Xiao C.Y., Yuhki K., Hara A., Fujino T., Kuriyama S., Yamada T. Prostaglandin E-2 protects the heart from ischemiareperfusion injury via its receptor subtype EP4. 2) (Stillman et al., 1998). Temporal expression of the PGE2 synthetic system in the kidney is associated with the time frame of renal developmental vulnerability to cyclooxygenase-2 inhibition. PGE2 stimulates the in vitro growth of human non-small cell lung cancer while an antagonist of EP4 or EP4 gene knockdown inhibits this growth. suppressor T cells that modulate the immune system to maintain tolerance to self-antigens and prevent autoimmune disease); b) stimulate Dendritic cells (i.e. Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP(4) receptor. Furthermore, the very recent 3D modeling of the human EP4 receptor and in silico docking experiments for PGE2 revealed the most likely binding sites of PGE2 on the 3D structure of EP4. aberrant proliferation of synovial tissue leading to joint destruction, endogenous PGE2 via activating its EP4 receptor, inhibited pannus growth and osteoclast activity (Shibata-Nozaki et al., 2011). Interestingly, the classical cAMP/PKA signaling module, eNOS or Rac1, PI3K or p38 kinases were not involved in this system. Released in response to various physiological and pathological stimuli they play essential roles in maintaining body homeostasis. A highly expressed prostaglandin E 2 (PGE 2) in tumor tissues suppresses antitumor immunity in the tumor microenvironment (TME) and causes tumor immune evasion leading to disease progression.In animal studies, selective inhibition of the prostaglandin E receptor 4 (EP4), one of four PGE 2 receptors, suppresses tumor growth, restoring the tumor immune response toward an antitumorigenic condition. However, their clinical use is considerably limited as they give rise to gastrointestinal, renal and cardiovascular complications, among others. 'Nancy Drew' Season 4: How to watch Episode 4 online, free live streams In particular, Gs stimulates adenyl cyclase to raise cellular levels of cAMP; cAMP activates PKA, a kinase which in turn activates signaling molecules, in particular, the transcription factor, CREB. Misoprostol, an EP 3 and EP 4 receptor agonist, to prevent ulcers; to induce labor in pregnancy, medical abortion, . Cyclooxygenase-2 and prostaglandin E2 (PGE2) levels are increased in colorectal cancers and a subset of adenomas. Cote S.C., Pasvanis S., Bounou S., Dumais N. CCR7-specific migration to CCL19 and CCL21 is induced by PGE(2) stimulation in human monocytes: involvement of EP(2)/EP(4) receptors activation. These receptors are coupled to different G proteins leading to subsequent activation of specific signal transduction pathways. Similarly, EP4 receptor stimulation resulted in cAMP/EPAC-mediated activation of RAP small GTPase and augmented migration of renal carcinoma cells (Wu et al., 2011). In contrast to these EP4 receptor-mediated, assumingly beneficial actions of PGE2, pathogenic roles of EP4 receptors have been implicated in cancer growth and metastasis, and in some inflammatory diseases. 'Project Runway' season 20, episode 4: How to watch for free (6/29/23) As a library, NLM provides access to scientific literature. Consequently, lubiprostone and other EP4 agonists could find therapeutic application in diseases with reduced airway fluid secretion. Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases. EP4 Receptor - an overview | ScienceDirect Topics Bruegel M., Ludwig U., Kleinhempel A., Petros S., Kortz L., Ceglarek U. Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients. Nitta M., Hirata I., Toshina K., Murano M., Maemura K., Hamamoto N. Expression of the EP4 prostaglandin E2 receptor subtype with rat dextran sodium sulphate colitis: colitis suppression by a selective agonist, ONO-AE1-329. Joy A.P., Cowley E.A. Poschke A., Kern N., Maruyama T., Pavenstadt H., Narumiya S., Jensen B.L. EP4 receptor becomes rapidly desensitized upon binding of G protein-coupled receptor kinases (GRK) to serine residues on the C-terminus. The first study to systematically compare the activation of Gs, Gi and -arrestin signaling pathways revealed characteristic differences between various ligands and native PGE2 (Leduc et al., 2009). Accordingly, smooth muscle cells of pulmonary vein express more EP4 mRNA than cells isolated from pulmonary artery (Foudi et al., 2008). miR-101modulates EP-4 receptor expression at the post-transcriptional [143] L-161,982, The EP4 receptor antagonist, blocks PGE2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells: Jiang G.-L., Nieves A., Im W.B., Old D.W., Dinh D.T., Wheeler L. The prevention of colitis by E prostanoid receptor 4 agonist through enhancement of epithelium survival and regeneration. Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G This latter finding suggests that murine studies cannot be easily extrapolated to human pathobiology. EP4 receptor as a novel promising therapeutic target in colon cancer Lubiprostone is currently approved for the treatment of chronic constipation in the U.S.A., Switzerland, United Kingdom and Japan. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day. An EP4 antagonist likewise prevented bladder hyperactivity induced by cyclophosphamide or PGE2 in rats (Chuang et al., 2012). Arns S., Gibe R., Moreau A., Morshed M.M., Young R.N. Prostaglandin E2 receptor 4 ( EP4) is a prostaglandin receptor for prostaglandin E2 (PGE 2) encoded by the PTGER4 gene in humans; [5] it is one of four identified EP receptors, the others being EP 1, EP 2, and EP 3, all of which bind with and mediate cellular responses to PGE 2 and also, but generally with lesser affinity and responsiveness, cer. Ninety five percent of animals were found to die due to patent ductus arteriosus, the fetal vessel that bridges the pulmonary and systemic circulation until birth (Segi et al., 1998). known phosphorylation targets of PKA that have been shown to mediate tube formation (Zhang & Daaka, 2011). EP4 receptors are expressed in enteroendocrine cells and stimulate the release of incretins, such as glucagon-like peptide-1, in vitro and in vivo in mice (Coskun et al., 2013). Moreover, activation of EP4 receptors attenuated the interaction of eosinophils with human pulmonary microvascular endothelial cells, with respect to adhesion under physiological flow conditions and transendothelial migration of eosinophils (Konya et al., 2011). That is, EP4 becomes insensitive to further activation and internalizes. 2) (Margan et al., 2012). However, the mechanisms of how elevation of intracellular cAMP levels exerts cardioprotection in ischemia has not yet been elucidated yet, but might reflect EP4 receptor-mediated vasodilator or platelet inhibitory responses as described below (Philipose et al., 2010). Recently, PGE2 was recognized to positively modulate the differentiation and activity of Th17 cells. Frolich S., Olliges A., Kern N., Schreiber Y., Narumiya S., Nusing R.M. EP4 receptors were found to abound on neurons and became markedly upregulated in endothelial cells after ischemia/reperfusion, suggesting that the dual EP4 receptor signaling of neurons and endothelial cells imparts cerebroprotection. 2) (Bastepe & Ashby, 1999; Desai et al., 2000). Negishi M., Sugimoto Y., Ichikawa A. Prostanoid receptors and their biological actions. Importantly, neutrophil infiltration into the liver was also found to be attenuated after EP4 receptor stimulation. Similar responses were recorded in human coronary artery endothelial cells. Laine L., Takeuchi K., Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Finally, ligand-biased selectivity of EP4 receptor signaling may exist for Gs, Gi and -arrestin-dependent pathways and should be taken into consideration when interpreting biological effects of different EP4 ligands. EP4 receptors facilitated pulmonary metastasis of lung carcinoma cells injected intravenously in mice and liver metastasis after intrasplenic injection of colon cancer cells (Yang et al., 2006). EP4 receptor expression in glomeruli is increased following salt deprivation as are PGE2-evoked cAMP and renin responses in juxtaglomerular cells (Jensen et al., 1999). In vitro, PGE2 acting via EP4 receptors augmented the survival of glomerular epithelial cells deprived of serum (Aoudjit et al., 2006), and an EP4 receptor agonist stimulated proliferation and decreased apoptosis of renal epithelial cells (Yamamoto et al., 2010). Activation of the EP(4) prostanoid receptor induces prostaglandin E(2) and pro-inflammatory cytokine production in human airway epithelial cells. Chell S.D., Witherden I.R., Dobson R.R., Moorghen M., Herman A.A., Qualtrough D. Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. Two different EP4-selective agonists, ONO AE1-734 and AGN205203, reversed the pathology of DSS colitis in wild-type mice, an effect that was strongly suppressed by an EP4 antagonist. Blenheim Vale: A Refresher for Endeavour's Final Season | PBS Takeuchi K., Yagi K., Kato S., Ukawa H. Roles of prostaglandin E-receptor subtypes in gastric and duodenal bicarbonate secretion in rats. Increased EP4 Receptor Expression in Colorectal Cancer Progression [6], To allow further studies of EP4 function, colonies obtained by cross-breeding the 5% of mice surviving EP4 deletion are used. In mice, EP4 receptor agonists reduce the acute rejection of transplanted hearts, prolong the survival of heart-transplanted animals, and reduce cardiac damage in a model of ischemic reperfusion injury but also stimulate cardiac hypertrophy accompanied by poor cardiac function. [11] Cardiac specific EP4 deficiency using Site-specific recombination by the Cre recombinase method to inactivate EP4 only in cardiac muscle causes a somewhat different form of cardiac disease, dilated cardiomyopathy, that develops within 2333 weeks after birth in mice. Melillo E., Woolley K.L., Manning P.J., Watson R.M., O'Byrne P.M. Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects. The EP4 receptor was initially described as a Gs protein-coupled receptor leading to stimulation of adenylate cyclase and elevation of intracellular cAMP levels (Coleman et al., 1994). In macrophages, the LPS-induced NF-B activation was observed to be blocked by PGE2. Differential regulation of renal prostaglandin receptor mRNAs by dietary salt intake in the rat. The patency of ductus arteriosus during the fetal period was presumed to be maintained principally by the dilator effect of the EP4 receptor, while its closure was thought to be induced by immediate withdrawal of the dilator prostaglandin PGE2 as well as active contraction exerted by increased oxygen tension (Smith, 1998). 2) (Fujino et al., 2003; Fujino & Regan, 2006). [8], In humans, mRNA for EP4 has been detected by Northern blotting in the heart and small intestine and to lesser extents in lung, kidney, thymus, uterus, dorsal root ganglions, and brain. Back To Main Menu Close. Physiological regulation of prostaglandins in the kidney. 1). Conditional deletion of neuronal or endothelial EP4 receptors aggravated the cerebral deficits and decreased cerebrovascular reperfusion in the same study. Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. [7] Gene [ edit] The PTGER3 gene is located on human chromosome 1 at position p31.1 (i.e. Accordingly, the EP4 agonist also delayed gastric emptying, but elevated blood glucose levels (Ohinata et al., 2006). Frontiers | Prostaglandin E Receptor 4 Antagonist in Cancer Additionally, the same EP4 agonists promoted angiogenesis in vivo (Rao et al., 2007; Zhang & Daaka, 2011). In the present study, . In mice, this is accomplished by turning off the mechanism which maintains the ductus's patency. PGE2 signaling through the EP4 receptor has previously been associated with colorectal tumorigenesis. Gs)-G beta-gammaes (i.e. Skip to Article. Furthermore, differential N-glycosylation also influences the maintenance of receptor surface expression (Ludwig et al., 2000). The ductus must close at birth to allow blood flow into the lungs. EP4 receptor over-expression resulted in the suppression of apoptosis in a cAMP/CREB-dependent manner, and enhanced anchorage-independent growth, of a human colon cancer cell line (Hawcroft et al., 2007). Chuang Y.C., Tyagi P., Huang C.C., Chancellor M.B., Yoshimura N. Mechanisms and urodynamic effects of a potent and selective EP4 receptor antagonist, MF191, on cyclophosphamide and prostaglandin E(2)-induced bladder overactivity in rats. PGE2 is formed from PGH2 by PGE synthases and binds to and activates four EP receptor subtypes, designated EP1 to EP4 receptors. In sharp contrast, systemic treatment of mice with the EP4 antagonist, ONO-AE3-208, or a heterozygous EP4+/ genotype decreased vascular inflammation and protected from angiotensin II-induced abdominal aortic aneurysm formation on an ApoE-deficient background (Cao et al., 2012; Yokoyama et al., 2012). In monocytes, EP4 receptor-mediated CREB activation and binding to the promotor of the chemokine receptor CCR7 enhances the expression of the receptor and augments the migration of the cells (Cote et al., 2009). Maruyama T., Kuwabe S.I., Kawanaka Y., Shiraishi T., Shinagawa Y., Sakata K. Design and synthesis of a selective EP4-receptor agonist. EP4 stimulation, among other functions, induces vascular relaxation mediated by cAMP, PKA and endothelial nitric oxide synthase (eNOS) (Hristovska et al., 2007), and angiogenesis via cAMP and PKA C (Zhang & Daaka, 2011) (Fig. Collectively, a large body of evidence suggests that EP4 agonists might be promising novel approaches to control vascular disease due to the broad biological functions of the EP4 receptor in vasculature. We'd like to inform you that we have updated our Privacy Notice to comply with Europe's new General Data Protection Regulation (GDPR) that applies since 25 May 2018 . Prostanoid signal transduction and gene expression in the endothelium: role in cardiovascular diseases. Smith & Dewitt, 1996; Park & Christman, 2006, O'Banion, 1999; Grosser et al., 2006; Zidar et al., 2009, Negishi et al., 1993; Sugimoto & Narumiya, 2007, Coleman et al., 1994; Nishigaki et al., 1995; Breyer et al., 1996, Johannessen et al., 2004; Johannessen & Moens, 2007, Desai & Ashby, 2001; Regan, 2003; Takayama et al., 2006, Bastepe & Ashby, 1999; Desai et al., 2000, Fujino et al., 2003; Fujino & Regan, 2006, Takayama et al., 2006; Minami et al., 2008; Prijatelj et al., 2012, Sheibanie et al., 2007; Sakata et al., 2010, Luft et al., 2002; Kabashima et al., 2003, Luft et al., 2002; Jing et al., 2003; Baratelli et al., 2005, Boniface et al., 2009; Napolitani et al., 2009, Pavord et al., 1993; Melillo et al., 1994; Aggarwal et al., 2010, Buckley et al., 2011; Benyahia et al., 2012, Kaufmann & Taubin, 1987; Bjarnason et al., 1993; Felder et al., 2000; Laine et al., 2008, Suzuki et al., 2001; Takeuchi et al., 2001, Kunikata et al., 2001; Kunikata et al., 2002, Takeuchi et al., 1997; Araki et al., 2000; Aihara et al., 2007, Kabashima et al., 2002; Nitta et al., 2002; Jiang et al., 2007, Gentile et al., 1981; Tada & Kishimoto, 1990, J.-i. PGE2 and EP4 receptors have been suggested to be involved in autosomal dominant polycystic kidney disease, as they induce proliferation and chloride secretion in polycystin-1 deficient epithelial cells, while inhibiting proliferation in polycystin-1 expressing cells (Liu et al., 2012). In B cell lymphomas, EP4 receptors are down-regulated and growth suppression is diminished (Murn et al., 2008). Sharma S., Yang S.C., Zhu L., Reckamp K., Gardner B., Baratelli F. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4. Tang E.H.C., Libby P., Vanhoutte P.M., Xu A. Anti-inflammation therapy by activation of prostaglandin EP4 receptor in cardiovascular and other inflammatory diseases. The cyclooxygenase inhibitor sulindac sulfide inhibits EP4 expression and suppresses the growth of glioblastoma cells.