PGE2 stimulates vascular smooth muscle cell proliferation via the EP2 receptor

Yau, Lorraine; Zahradka, Peter

doi:10.1016/s0303-7207(03)00096-0

Cited by 30 publications

(23 citation statements)

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“…49 It is expressed in both endothelial cells and VSMCs. 47,50 Although activation of EP2 in endothelial cells may increase monocyte adhesion and possibly initiate vascular inflammation in the early stage of atherosclerosis, 50 our study clearly demonstrates that EP2 is protective in restenosis development. First, EP2 expression was significantly upregulated in injured arteries and in PDGF-treated VSMCs.…”

Section: Discussionmentioning

confidence: 66%

“…In addition, although the effect of PGE 2 on VSMC proliferation has been reported by several groups, the results are inconsistent, with both inhibitory and stimulatory effects reported. [17][18]47,48 PGE 2 exerts its biological roles by 4 EP receptors, EP1 to EP4. Activation of EP receptors, with characteristic vascular distribution, evokes receptor-specific signaling pathways and results in distinct biological consequences.…”

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confidence: 99%

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Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Zhu

Xue

Zhao

et al. 2011

ATVB

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Objective-Restenosis after angioplasty remains a major clinical problem. Prostaglandin E 2 (PGE 2 ) plays an important role in vascular homeostasis. The PGE 2 receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. Methods and Results-Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2ϩ/ϩ) and EP2 gene-deficient (EP2Ϫ/Ϫ) mice. In EP2ϩ/ϩ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2Ϫ/Ϫ mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2Ϫ/Ϫ mice than in those of EP2ϩ/ϩ mice. Activation and overexpression of EP2 attenuated PDGF-BB-elicited cell proliferation and migration, induced G 1 3 S-phase arrest and reduced PDGF-BB-stimulated extracellular signal-regulated kinase phosphorylation in EP2ϩ/ϩ VSMCs. Conclusion-These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty. (Arterioscler Thromb Vasc Biol. 2011;31:1739-1747.)Key Words: angioplasty Ⅲ eicosanoids Ⅲ prostaglandins Ⅲ receptors Ⅲ restenosis P ercutaneous transluminal coronary angioplasty (PTCA) has been widely used for treating coronary atherosclerosis. However, many patients undergoing PTCA experience postangioplasty restenosis. 1 Although new devices for dilatation of stenosed arteries have lowered the incidence of acute complications, restenosis remains a major obstacle in the long-term outcome of PTCA interventions. 2 Restenosis is defined as the healing response of the arterial wall to mechanical injury and consists of 2 main processes: neointimal hyperplasia (smooth muscle migration/proliferation and extracellular matrix deposition) and vessel remodeling. 3 Platelet-derived growth factor-BB (PDGF-BB), an important growth factor released from platelets and leukocytes, plays a critical role in intimal hyperplasia after vascular injury. 4,5 An enormous amount of research has elucidated the molecular pathways involved in neointimal formation and vascular remodeling after vascular injury and has greatly advanced our understanding of the mechanisms contributing to the pathogenesis of restenosis. 6 -8 These efforts have led to many new strategies for effective prevention and treatment options for restenosis.Prostaglandin E 2 (PGE 2 ), a major arachidonic acid metabolite, is produced in the vasculature via a mechanism dependent on cyclooxygenase (COX) and prostaglandin E synthase. PGE 2 has important roles in the regulation of blood pressure, inflammatory response, immune response, an...

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Section: Discussionmentioning

confidence: 66%

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confidence: 99%

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Zhu

Xue

Zhao

et al. 2011

ATVB

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“…Thus, hepatocytes differ from various other cell types in which EP2 and/or EP4 receptors appear to mediate the growth-promoting effects of prostaglandins (Sheng et al, 2001;Yau and Zahradka, 2003;Chang et al, 2005;Fulton et al, 2006). We based this conclusion on the following observations.…”

Section: Discussionmentioning

confidence: 99%

“…Prostaglandins stimulate proliferation in a number of different cell types (Watanabe et al, 1994;Sheng et al, 2001;Yau and Zahradka, 2003;Chang et al, 2005;Krysan et al, 2005), including neonatal and adult rat hepatocytes (Andreis et al, 1981;Skouteris et al, 1988;Refsnes et al, 1994;Hashimoto et al, 1997;Kimura et al, 2001). In primary cultures of rat hepatocytes, prostaglandins exert a small stimulatory effect on DNA synthesis on their own compared with the strong stimulation of DNA synthesis induced by mitogens, such as epidermal growth factor (EGF), and they act mainly by enhancing the growth stimulatory effect of mitogens .…”

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Prostaglandins Enhance Epidermal Growth Factor-Induced DNA Synthesis in Hepatocytes by Stimulation of E Prostanoid 3 and F Prostanoid Receptors

Meisdalen

Dajani²,

Christoffersen³

et al. 2007

J Pharmacol Exp Ther

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Prostaglandins stimulate hepatocyte proliferation in vivo and in vitro. We have examined the role of E prostanoid (EP) and F prostanoid receptors (FP) in enhancing the growth-stimulatory effect of epidermal growth factor (EGF) in cultured hepatocytes. The EP2 receptor agonist butaprost had no significant effect on EGF-induced DNA synthesis. EP1 receptor-selective antagonists did not affect the enhancement by prostaglandin E 2 of EGF-stimulated DNA synthesis. Sulprostone, misoprostol, and fluprostenol strongly enhanced DNA synthesis and inhibited glucagon-stimulated cAMP accumulation, indicating that they all activated EP3 receptors. Combining fluprostenol with misoprostol, but not with sulprostone, resulted in partially additive effects on DNA synthesis, suggesting that both EP3 and FP receptors are involved. Combining sulprostone with misoprostol did not result in additive effects on DNA synthesis, suggesting that EP4 receptors were not involved. We conclude that, although a minor effect is exerted by FP receptors, the growth-stimulatory effects of prostaglandins in rat hepatocytes are mediated mainly by EP3 receptors. We have found no evidence of EP1 receptor involvement.

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“…The fact that EP2 immunoreactivity was not observed in the vasculature whereas EP2 transcripts were detected in sampled JG cells could be due to a lower sensitivity of immunostaining compared with PCR, because data at the functional level suggest that EP2 receptors contribute significantly to PGE 2 -mediated depressor effects on renal and systemic hemodynamics (1,17,23,34,44). EP2 binding sites are present in vascular smooth muscle from several vascular beds (24,43). EP2 is by far the least abundant EP receptor subtype in kidney and vasculature in comparative assays (19,20,44).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E₂EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells

Friis

Stubbe²,

Uhrenholt³

et al. 2005

American Journal of Physiology-Renal Physiology

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Friis, Ulla G., Jane Stubbe, Torben R. Uhrenholt, Per Svenningsen, Rolf M. Nü sing, Ole Skøtt, and Boye L. Jensen. Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells. Am J Physiol Renal Physiol 289: F989 -F997, 2005. First published June 28, 2005; doi:10.1152 doi:10. /ajprenal.00201.2005 and PGI2 stimulate renin secretion and cAMP accumulation in juxtaglomerular granular (JG) cells. We addressed, at the single-cell level, the receptor subtypes and intracellular transduction mechanisms involved. Patch clamp was used to determine cell capacitance (Cm), current, and membrane voltage in response to PGE2, EP2 and EP4 receptor agonists, and an IP receptor agonist. PGE2 (0.1 mol/l) increased Cm significantly, and the increase was abolished by intracellular application of the protein kinase A antagonist Rp-8-CPT-cAMPS. EP2-selective ligands butaprost (1 mol/l), AE1-259-01 (1 nmol/l), EP4-selective agonist AE1-329 (1 nmol/l), and IP agonist iloprost (1 mol/l) significantly increased Cm mediated by PKA. The EP4 antagonist AE3-208 (10 nmol/l) blocked the effect of EP4 agonist but did not alter the response to PGE2. Application of both EP4 antagonist and EP2-antagonist AH-6809 abolished the effects of PGE2 on Cm and current. EP2 and EP4 ligands stimulated cAMP formation in JG cells. PGE2 rapidly stimulated renin secretion from superfused JG cells and diminished the membrane-adjacent granule pool as determined by confocal microscopy. The membrane potential hyperpolarized significantly after PGE2, butaprost, AE1-329 and AE1-259 and outward current was augmented in a PKA-dependent fashion. PGE2-stimulated outward current, but not Cm change, was abolished by the BKCa channel inhibitor iberiotoxin (300 nmol/l). EP2 and EP4 mRNA was detected in sampled JG cells, and the preglomerular and glomerular vasculature was immunopositive for EP4. Thus IP, EP2, and EP4 receptors are associated with JG cells, and their activation leads to rapid PKA-mediated exocytotic fusion and release of renin granules.cyclooxygenase; capacitance; kidney; current; potential RENIN IS STORED AND RELEASED by juxtaglomerular granular (JG) cells in the distal part of the afferent glomerular arterioles. The activity of the circulating renin-angiotensin-aldosterone system is determined predominantly by the rate of renin secretion from the JG-cells. Cyclooxygenase (COX) activity supports basal renin release in vivo (32). The increase in renin expression and secretion seen in response to a low epithelial NaCl transport rate across the thick ascending limb of Henle's loop (TALH) is significantly attenuated by COX blockers, in both experimental animals and humans (10,22,31,40,41). Expression of the inducible COX enzyme COX-2 correlates inversely with NaCl transport across TALH, and COX-2 activity generates predominantly PGE 2 at this site (5,9,29,41,42). Compared with the detailed insight into the regulation of prostaglandin synthesis by the epithelium, relatively less is known ...

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PGE2 stimulates vascular smooth muscle cell proliferation via the EP2 receptor

Cited by 30 publications

References 43 publications

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Prostaglandins Enhance Epidermal Growth Factor-Induced DNA Synthesis in Hepatocytes by Stimulation of E Prostanoid 3 and F Prostanoid Receptors

Prostaglandin E₂EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells

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PGE2 stimulates vascular smooth muscle cell proliferation via the EP2 receptor

Cited by 30 publications

References 43 publications

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Prostaglandins Enhance Epidermal Growth Factor-Induced DNA Synthesis in Hepatocytes by Stimulation of E Prostanoid 3 and F Prostanoid Receptors

Prostaglandin E2EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells

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Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Prostaglandin E₂EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells