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(Circulation Research. 2000;87:504.)
© 2000 American Heart Association, Inc.

Cellular Biology

Human Vascular Smooth Muscle Cells but Not Endothelial Cells Express Prostaglandin E Synthase

Marta Soler, Mercedes Camacho, José-Román Escudero, Miguel A. Iñiguez, Luís Vila

From the Laboratory of Inflammation Mediators (M.S., M.C., J.-R.E., L.V.), Institute of Research of Hospital Santa Creu i Sant Pau, Barcelona, and Centro de Biología Molecular "Severo Ochoa" Centro Superior de Investigaciones Cienticas (M.A.I.), Madrid, Spain.

Correspondence to Dr Luís Vila, H.S. Creu i S. Pau (Antigua Guardería), S. Antonio M^a Claret 167, 08025 Barcelona, Spain. E-mail luisvila{at}retemail.es

	Abstract

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Abstract—In a previous work, we postulated that endothelial cells possess only the following 2 enzymes involved in prostanoid synthesis: cyclooxygenase and prostacyclin synthase. The present work focused on investigating the expression of prostaglandin (PG) E synthase (PGES) in vascular cells. After incubation of vascular smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) with [¹⁴C]arachidonic acid, the profile of prostanoid synthesis was assessed by HPLC. Untransformed PGH₂ released by the cells was evaluated as the difference in the formation of PGF₂ in the incubations performed in the presence and in the absence of SnCl₂. Resting SMCs and SMCs stimulated with phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), interleukin (IL)-1ß, and tumor necrosis factor (TNF)- formed PGE₂ and PGI₂ (evaluated as 6-oxo-PGF₁), and in the presence of SnCl₂ only a small amount of PGE₂ was deviated toward PGF₂. In contrast, resting and stimulated HUVECs produced PGI₂, PGE₂, PGF₂, and PGD₂, and SnCl₂ completely diverted PGE₂ and PGD₂ toward PGF₂. Reverse transcriptase–polymerase chain reaction analysis shows that mRNA encoding for PGES was not present in HUVECs and in endothelial cells from saphenous vein. Nevertheless, PGES was expressed in SMCs and induced by IL-1ß and TNF-, and by PMA and LPS, although to a lesser extent. Whereas SMC stimulation led to an increase in the synthesis of PGE₂ and PGI₂ but not of untransformed PGH₂, stimulation of endothelial cells resulted in an enhanced release of the vasoconstricting prostanoid PGH₂.

Key Words: prostaglandin E synthase • endothelium • smooth muscle • prostanoid • cytokine

	Introduction

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The potent relaxing and platelet antiaggregation agent prostaglandin (PG) I₂ (also termed prostacyclin) is the characteristic prostanoid released by vascular endothelial¹ and smooth muscle cells (SMCs).² PGE₂ is also a major prostanoid found to be produced in vitro by vascular cells in response to different agents, which include exogenously added arachidonic acid (AA) and several agonists.^{1 3 4 5} Cyclooxygenase (COX, also termed PGH synthase) is the first enzyme in the biosynthesis of prostanoids. Two COX isoforms have been described. COX-1 is expressed in a constitutive manner, whereas COX-2 is the isoenzyme inducible by mitogens and overexpressed in inflammatory processes.⁶ COX catalyzes the transformation of AA to PGH₂, which has constricting and platelet-activating properties, because both thromboxane A₂ and PGH₂ share the same receptor.⁷ Prostacyclin synthase (PGI synthase; PGIS) catalyzes the subsequent transformation of PGH₂ into PGI₂. Isomerization of PGH₂ to PGE₂ may occur spontaneously⁸ or may be enzymatically catalyzed by a PGE synthase (PGES). The enzyme responsible for this isomerization was little known until the recent report by Jakobsson et al,⁹ who identified and characterized the human PGES as a membrane-bound enzyme of which the activity is glutathione-dependent and inducible by interleukin (IL)–1ß.

We reported that endothelial cells released untransformed PGH₂ when COX activity increased and PGIS decreased as a result of the action of IL-1ß.^{5 10} Although endothelial cells produced PGE₂ as a major prostanoid, in particular after cytokine stimulation, on the basis of indirect evidence we postulated that endothelial cells possess only 3 enzymes involved in the biosynthesis of prostanoids COX-1, COX-2, and PGIS.⁵ Because expression of PGES could not only modulate synthesis of PGE₂ but could also modulate the release of untransformed PGH₂ or even PGI₂ by diverting metabolism of PGH₂, this study was conducted to investigate the expression of PGES on vascular cells and its modulation by mitogens and cytokines.

	Materials and Methods

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Cell Culture and Treatment
Human umbilical vein endothelial cells (HUVECs) were cultured as previously described.¹¹ HUVECs in first passage were maintained without heparin and endothelial cell growth factor for 48 hours before the addition (or not) of 10 nmol/L phorbol 12-myristate 13-acetate (PMA, Sigma), 10 U/mL human recombinant IL-1ß (Boehringer Mannheim), 20 ng/mL recombinant human tumor necrosis factor (TNF)- (Promega), or 100 µg/mL of lipopolysaccharide (LPS, Escherichia coli serotype 0111:B4, Sigma) in M199 containing 1% FBS and maintained for 6 hours until incubation with [¹⁴C]AA or mRNA extraction. Saphenous vein endothelial cells (SVECs) were obtained by treatment of the endothelial surface with a solution of collagenase (0.07% wt/vol) for 15 minutes. SVECs were scraped carefully, cultured, and treated as described for HUVECs. SVECs were used in second passage.

Human dermal fibroblasts were isolated and cultured as described.¹² Cells in passages 4 to 6 were maintained with 1% FBS for 48 hours before treatment with PMA, IL-1ß, TNF-, or LPS as described above.

SMCs were isolated from human popliteal artery by an explant procedure. The artery was split longitudinally, and the endothelium was removed by gently scraping. The tissue was minced and seeded onto the culture surface in a small volume of DMEM containing 10% FBS. SMCs were characterized by -actin–positive staining. Cells in passages 4 to 7 were maintained with 1% FBS for 48 hours before treatment with PMA, IL-1ß, TNF-, or LPS as described above.

Determination of AA Metabolism in the Presence or Absence of SnCl₂
After treatment with the stimuli, cells were incubated in the presence of 25 µmol/L [¹⁴C]AA (55 to 58 mCi/mmol, Amersham) as described.⁵ To estimate the untransformed PGH₂ released, we calculated the difference between the PGF₂ peak of the samples from cells incubated as aforementioned and cells incubated in the presence of 200 µg/mL SnCl₂ as described.⁵ Prostanoids were analyzed by HPLC as described.¹³

Expression of PGES
After cell treatment with the stimuli, total RNA was isolated and reverse-transcribed into cDNA and then subjected to a polymerase chain reaction (PCR) protocol as previously described for COX-1 and COX-2.¹² Serial half-dilutions of the cDNA were performed to test linearity. Specific primers (Progenetic SL) for PCR based on the open reading frame of the microsomal glutathione-dependent PGES sequence described⁹ were synthesized. The sequence of the sense and antisense primers for human PGES were 5'-CTCTGCA-GCACGCTGCTGG-3' (sense) and 5'-GTAGGTCACGGAG-CGGATGG-3' (antisense). This primer pair yielded an amplified product of the expected size of 344 bp. After an initial denaturation for 5 minutes at 94°C, 27 cycles of amplification (94°C for 45 seconds, 65°C for 45 seconds, and 72°C for 45 seconds) were performed, followed by a 10-minute extension at 72°C, for all the samples. The amplification products were separated by electrophoresis, and the radioactivity associated with the specific band was evaluated and normalized to GAPDH as previously described.¹²

	Results

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Prostanoid synthesis by SMCs was characterized by the formation of PGE₂ and PGI₂ (evaluated as 6-oxo-PGF₁); PGF₂ was not detected in the absence of SnCl₂. When SnCl₂ was present in the incubation mixture, only a small amount of PGE₂ was deviated toward PGF₂, whereas formation of PGI₂ was not modified by SnCl₂. For comparative purposes human dermal fibroblasts were included in the study, their prostanoid profile being similar to that of SMCs (Figure 1). PMA, LPS, IL-1ß, and TNF- significantly increased the formation of PGE₂ in SMCs (Table). Formation of PGI₂ was significantly increased only by PMA, IL-1ß, and TNF-.

View larger version (19K): [in this window] [in a new window]   Figure 1. Representative chromatograms of samples from IL-1ß–treated cells incubated with [14C]AA in the absence and in the presence of SnCl2.

View this table: [in this window] [in a new window]   Table 1. Prostanoid Formation by Resting and Stimulated HUVECs and SMCs from [14C]AA

As expected, resting and treated HUVECs incubated with [¹⁴C]AA produced PGI₂ (evaluated as 6-oxo-PGF₁), PGE₂, PGF₂, and PGD₂ as prostanoids. Cell treatment with the stimuli caused an increased production of prostanoids in HUVECs. Nevertheless, the net effect of PMA, IL-1ß, TNF-, and LPS on each particular prostanoid was not uniform (Table). PGE₂ and PGD₂ were the main prostanoids increased by all of the inductors (Table). The formation of PGI₂ was only minimally modified by the presence of SnCl₂ in the medium. In contrast, PGE₂ and PGD₂ completely disappeared in the samples containing SnCl₂, and the levels of PGF₂ increased concomitantly (Figure 1).

Reverse transcriptase (RT)–PCR analysis of mRNA encoding for PGES showed that the enzyme was expressed in SMCs and dermal fibroblasts but not in HUVECs and in SVECs. PGES was strongly induced by IL-1ß and TNF-, with IL-1ß being the most potent (Figure 2). PMA and LPS also significantly induced PGES but to a lesser extent. Twenty-seven cycles of PCR were usually performed for linearity, although no band corresponding to PGES was detected in HUVECs and SVECs even after 35 cycles of PCR (not shown).

View larger version (56K): [in this window] [in a new window]   Figure 2. Levels of specific mRNA for PGES expression normalized with respect to GAPDH in cells untreated (resting) and treated with PMA, IL-1ß, TNF-, or LPS. Data are mean±SD; n=6. *P<0.05, **P<0.001 when compared with resting cells (Student-Newman-Keuls test). Representative photographs of PCR electrophoresis are also shown.

	Discussion

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The present results clearly indicate that endothelial cells from fetal and adult vessels did not express PGES even after treatment with the cytokines, PMA, or LPS. It is well known that culture conditions influence AA metabolism in endothelial cells. It has been reported that COX is downregulated by endothelial cell growth factor and heparin.^{14 15 16 17 18} Under our experimental conditions, endothelial cells were maintained without heparin and endothelial cell growth factor for 48 hours before the addition (or not) of PMA, IL-1ß, TNF-, or LPS to maximize prostanoid formation. An even more important factor that regulates AA metabolism in cultured endothelial cells is the number of subcultivations. It has been reported that subcultivation negatively influences PGI₂ formation by endothelial cells.^{19 20} Indeed, we also observed that HUVECs lose their ability to form PGI₂ as the number of passages increase. The loss of activities of both COX and PGIS was related to a diminution of the expression of COX-1 and PGIS, with the loss of PGIS being faster than that of COX-1 in terms of mRNA (unpublished results). The present results were obtained from experiments performed with HUVECs and SVECs at first and second passage, respectively, to maximize COX and PGIS activities and to prevent the hypothetical loss of PGES expression with the number of passages.

In contrast, PGES was expressed in resting and stimulated SMCs and dermal fibroblasts. Consistently with the report of Jakobsson et al,⁹ PGES was inducible by IL-1ß in SMCs and fibroblasts but also by TNF-, PMA, and LPS, which indicated that it is probably induced under inflammatory conditions. Our results are also consistent with previous reports that PGE₂ is the most commonly induced prostanoid by IL-1ß in SMCs, although in these works PGES expression was not analyzed.^{21 22} Matsumoto et al²³ observed that LPS induced COX-2 expression and enhanced PGES activity in rat macrophages. The fact that not only PGE₂ but also PGI₂ was increased by PMA, IL-1ß, and TNF- in SMCs was due to the induction of COX-2 (evaluated by RT-PCR and Western blotting [not shown]) by these agents, which indicates that formation of PGI₂ in SMCs is limited by COX activity rather than by PGIS.

PGIS and PGES compete for the substrate because both PGIS and PGES have the same substrate (PGH₂) and, like COX, both are located in the microsomal fraction. On the other hand, whereas PGES is an inducible enzyme,⁹ PGIS is not.⁵ The substrate distribution between PGIS and PGES is primarily governed by the relative affinity each enzyme has for the substrate. Experiments performed with preparations of purified bovine PGIS showed a K_m of 7.3 to 9 µmol/L.^{24 25} K_m values for PGES purified from rat tissues were between 25.5 and 82.6 µmol/L,²⁶ and when purified from sheep vesicular glands, the K_m value was 40 µmol/L.²⁷ Unfortunately, there are still no data in the literature about the kinetic parameters of the human enzymes or even kinetic studies performed with PGIS and PGES preparations of the same species. In any case, theoretically, a modification in the proportion of PGIS and PGES molecules would probably influence the relative amount of PGI₂ and PGE₂ formed in a particular cell that expresses both enzymes. Hence, the induction of PGES could indirectly influence PGI₂ formation. Results from experiments incubating cells with labeled AA showed a PGE₂/PGI₂ ratio of 1.8±0.2 and 2.2±0.5 (mean±SD, n=6) in controls and in IL-1ß–treated SMCs, respectively. This variation was in fact less apparent than expected. This could be due to the fact that other factors such as a different velocity of suicide inactivation of the PGIS and PGES and the total COX activity could also influence the relative amount of PGI₂ and PGE₂ formed under a particular condition.

More apparent was the effect of PGES expression on the release of untransformed PGH₂, which has activity opposite that of PGI₂. Although COX-2 was induced (not shown), treatment of SMCs with IL-1ß resulted in a significant decrease in their ability to release untransformed PGH₂, which was likely a result of a concomitant induction of PGES. In contrast, COX-2 induction in HUVECs resulted in an enhanced ability to release the vasoconstricting prostanoid PGH₂.⁵ The present results suggest that SMCs do not contribute to the release of PGH₂ even under inflammatory conditions and reinforce the concept that release of PGH₂ by vascular endothelial cells is exclusively regulated by the ratio of COX to PGIS activity.^{5 10} More research is needed to ascertain PGES expression under pathological conditions and in other endothelial cell phenotypes such as capillary endothelial cells.

	Acknowledgments

 
This work was supported by grants from Institut de Recerca of the Hospital Santa Creu i Sant Pau and from SAF96-0138. We thank Dr Manuel Fresno for his critical reading of the manuscript and Cristina and Esther Gerbolés for their technical assistance.

Received May 17, 2000; revision received July 10, 2000; accepted July 31, 2000.

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