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(Circulation Research. 2002;90:678.)
© 2002 American Heart Association, Inc.

Cellular Biology

Nucleotide Receptors Involved in UTP-Induced Rat Arterial Smooth Muscle Cell Migration

Xavier Pillois, Hervé Chaulet, Isabelle Belloc, Françoise Dupuch, Claude Desgranges, Alain-Pierre Gadeau

From INSERM U441, Pessac, France.

Correspondence to Alain-Pierre Gadeau, Avenue du Haut Lévêque, 33600 Pessac, France. E-mail alain.gadeau{at}bordeaux.inserm.fr

	Abstract

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Many factors have been shown to be involved in the development of hyperplasic lesions of vessels, but the role of extracellular nucleotides remains largely unknown. The presence of P2Y and P2X nucleotide receptors on arterial endothelial and smooth muscle cells suggests a potential role for nucleotides in the vessel pathophysiology. Although the role of P2X in physiology of vessels is well documented, that of P2Y is not completely understood. We recently demonstrated that extracellular nucleotides, and particularly UTP, induced migration of cultured arterial smooth muscle cells (ASMCs). This migration is dependent on osteopontin expression and involves the Rho and mitogen-activated protein (MAP) kinase pathways. An important question is to determine the specific role of the different P2Y receptors of rat ASMCs in the UTP-induced migration process. Therefore, we first quantified mRNA levels of P2Y₂, P2Y₄, and P2Y₆ nucleotide receptors in cultured rat ASMCs by a competitive RT-PCR approach and demonstrated that P2Y₂ is the most highly expressed among these receptors potentially involved in the UTP-mediated response. In addition to UTP, UDP also induced ASMC migration even when UTP regeneration was inhibited, suggesting the involvement of UDP receptor P2Y₆. Moreover, suramin, a specific antagonist of rat P2Y₂ receptor, acted as an inhibitor of UTP-induced migration. Taken together, these results suggest a prominent role for the UTP receptor, P2Y₂, and for the UDP receptor, P2Y₆, in UTP-induced rat ASMC migration.

Key Words: purinergic receptors • migration • UTP • smooth muscle cells

	Introduction

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The important role of arterial smooth muscle cell (ASMC) migration and proliferation in arterial hyperplasia is well documented in experimental models for atherosclerosis and restenosis.¹ Although proliferation can be easily demonstrated in arterial injury models, evidence for in vivo ASMC migration is suggested only by the presence of these cells in the intima.

Many factors have been shown to be involved in the development of hyperplasic lesions of vessels.² Among these, the role of extracellular nucleotides remains largely unknown. Two families of receptors have been identified for these compounds: inotropic P2X receptors and metabotropic P2Y receptors. The presence of P2Y and P2X receptors on endothelial and ASMCs suggests a potential role for nucleotides in the arterial pathophysiology. Although the role of P2X receptors in vasomotoricity of vessels is well documented, that of P2Y receptors in the vessel wall is still under investigation.

Several studies have shown that ATP and UTP binding to P2Y G protein-coupled receptors mediates ASMC activation,³ cell-cycle progression,⁴ and cell proliferation.^5,6 Moreover, we recently demonstrated that UTP induces ASMC migration and that this migration is dependent on osteopontin expression and involves the Rho and mitogen-activated protein (MAP) kinase pathways.⁷

The overexpression of the ATP/UTP P2Y₂ receptor in ASMCs of rat aortic intimal lesion⁸ and in ASMCs of human coronary atherosclerotic/restenotic lesions (C. Seye and C. Desgranges, unpublished results, 1997) underlines the potential role of nucleotides in pathological processes.

In mammals, the P2Y family currently includes six receptors P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁ (for review, see Reference 3) and the recently cloned platelet receptor P2Y₁₂.⁹ Their nucleotide agonist specificity has been extensively studied mainly on calcium flux responses of transfected cells, and these studies have demonstrated a selective purine response of ADP for P2Y₁ and P2Y₁₂, of ATP for P2Y₁₁, a selective UDP response for P2Y₆, and a mixed purine and pyrimide selectivity for P2Y₂ and the rat P2Y₄.³

A further issue concerns the specific role of the different P2Y receptors of rat ASMCs in UTP-induced migration. For this purpose, we first evaluated the expression of UTP/UDP-activated receptors by measuring the level of mRNA of P2Y₂, P2Y₄, and P2Y₆ receptors in rat ASMCs using competitive RT-PCR. Then, we compared the ability of UTP and UDP to induce ASMC migration with the aim of discriminating the specific role of these receptors in this process. Taken together, these results suggest a prominent role of P2Y₂ and P2Y₆ in UTP-induced rat ASMC migration.

	Materials and Methods

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Cell Culture
Rat ASMCs were prepared from thoracic aortas of Wistar rats as previously described.¹⁰ Cells were cultured in DMEM containing 5% FCS, 150 mmol/L HEPES, 100 U/mL penicillin, and 100 µg/mL streptomycin (Life Technologies, Cergy Pontoise, France). ASMCs from passages 6 to 12 were used.

Migration Assay
Cell migration was performed using the Transwell system (Costar), which allows cells to migrate through 8-µm-pore sized polycarbonate membrane as previously described.⁷ Briefly, 50 000 cells were added to the upper chamber of the Transwells. The lower chamber was filled with 600 µL serum-free DMEM containing or not containing nucleotides (ATP, ADP, UTP, UDP, UMP, ,ß-methylene-ATP) or uridine in appropriate concentrations. After a 6-hour incubation, cells present beneath the membrane were stained with hemalum and counted in 10 high-power microscopic fields. Analysis was performed on 3 wells for each condition and each experiment was repeated at least 3 times.

In experiments using nucleoside-5'-diphosphate kinase (NDPK), UTP or UDP solutions (10 µmol/L) were preincubated 15 minutes at room temperature with 2.5 U/mL NDPK and 100 µmol/L CTP before addition in the lower chamber of Transwells and migration assay. In experiments using hexokinase, UTP or UDP solutions (1 mmol/L) were preincubated during 1 hour at 37°C with 10 U/mL hexokinase. Migration tests were performed in the presence of 10 mmol/L pretreated nucleotide solution and 1 U/mL hexokinase. Full nucleotide transformation by NDPK plus CTP or by hexokinase was checked by HPLC. In experiments using suramin, ASMCs were preincubated 10 minutes with the inhibitor before loading in the upper chamber and performing migration test as described above. Enzymes, nucleotides, nucleosides, and suramin were from Sigma (St Quentin Fallavier, France).

Competitive RT-PCR
Purification of mRNA, cDNA synthesis, and PCR were performed as previously described.⁸ For competitive PCR, the specific competitor of P2Y receptor cDNA at various concentrations and the cellular cDNA were added to the PCR mix in a final volume of 25 µL and coamplified. Competitive templates were either mutated DNA obtained by site-directed mutagenesis or orthologues of the target cDNA that differ from the respective rat P2Y receptor sequence by the presence or absence of a specific restriction site (Table). Thirty to forty amplification cycles were used with an annealing temperature of 66°C for P2Y₁, P2Y₄, and P2Y₆ and of 62°C for P2Y₂ receptors. Cellular cDNA and competitor PCR products were separated on a 1.5% agarose gel electrophoresis after hydrolysis by specific restriction enzymes. Equipotent ethidium bromide fluorescence of competitor and cellular cDNA PCR products indicates identical template concentration in the starting solution. Each experiment was done in triplicate.

View this table: [in this window] [in a new window]   Table 1. Primer Sequences, Mimic Characteristics, and Amplification Product Lengths

Statistics
ANOVA and unpaired Student’s t test were performed for statistical analysis. A probability value less than 0.05 was considered statistically significant. Data are expressed as mean±SD.

	Results

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Quantification of P2Y mRNA Expression
The mRNA amount of P2Y₁, P2Y₂, P2Y₄, and P2Y₆ receptors in cultured ASMCs was evaluated by competitive RT-PCR. Figure 1 shows gel electrophoresis of PCR products obtained with different competitor concentrations and demonstrated that P2Y receptor mRNA was expressed at very different levels in the cells. The estimated amount of P2Y₂ receptor mRNA was 10-fold that of P2Y₆ receptor, itself 10-fold higher than that of P2Y₄ receptor. P2Y₁ receptor expression was 100-fold lower than that of P2Y₄ receptor.

View larger version (70K): [in this window] [in a new window]   Figure 1. P2Y1, P2Y2, P2Y4, and P2Y6 receptor expression in cultured rat ASMCs. Purinergic receptor cDNA quantification was performed by competitive PCR. Competitor of each P2Y receptor, added from 10-12 to 10-5 µg/µL to the PCR mix test, was coamplified with respective cellular cDNA. PCR products from competitor (black arrowheads) were separated from specific cDNA (white arrowheads) by 1.5% agarose gel electrophoresis. The white rectangle on each image delineates the reversal point of amplification of specific cDNA versus competitor. L indicates 100-bp ladder; C, control lane without competitor added in the test tube.

Effect of UTP and UDP on ASMC Migration
At least three receptors, P2Y₂, P2Y₄, and P2Y₆, are known to respond to pyrimidine nucleotides and could mediate the ASMC migration response induced by UTP or its immediate catabolite UDP. To determine the receptor(s) involved in this process, we compared the effect of the uridylic family UTP, UDP, UMP, and uridine and that of ATP and ADP on ASMC migration. Figure 2 demonstrates that neither UMP nor uridine has migratory potential. In contrast, UDP induced ASMC migration but to a lesser degree than UTP. The UDP response was 50% that of UTP. The specific potential of UTP and UDP by themselves needs to be evaluated because UTP and UDP can be converted to each other. Indeed UTP can be catabolized by ectonucleotidases into UDP, and UDP can be converted into UTP by extracellular ectonucleotide diphosphokinase.¹¹

View larger version (13K): [in this window] [in a new window]   Figure 2. Effect of uridylic nucleotide and nucleoside family compounds on ASMC migration. ASMCs (5x104 cells) were seeded in the upper chamber of Transwells and 10 µmol/L each of UTP, UDP, UMP, and uridine were added to the lower chamber of Transwells. Migration was evaluated after a 6-hour incubation. Data represent mean±SD of the relative migration compared with the control from 3 experiments performed in triplicate. The control (white bar) represents cell migration without nucleotide/nucleoside addition in lower chambers. *P<0.05 vs control; #P<0.05 vs UTP.

To confirm the involvement of UTP-specific receptors, the migration test was performed in conditions limiting the involvement of UDP. To this end, the migration test was done in the presence of NDPK and CTP in the cultured medium so that UDP generated by UTP catabolism was immediately transformed into UTP. The efficiency of this process was assessed by determining the nucleotide concentration in the cultured medium by HPLC (not shown). The UTP solution added to the bottom of the migration chamber was also treated with NDPK to eliminate UDP contamination. In these conditions, UTP-mediated ASMC migration could be entirely attributed to this nucleotide. Moreover, addition of NDPK to the medium of UDP-stimulated ASMCs led to an increased chemotactic activity, demonstrating that UTP is a more potent chemoattractant than UDP for ASMCs (Figure 3A).

View larger version (17K): [in this window] [in a new window]   Figure 3. Both UTP and UDP induce ASMC migration. ASMC migration was evaluated after a 6-hour incubation with UTP or UDP 10 µmol/L in the presence or absence of NDPK (2.5 U/mL) and CTP 100 µmol/L (A) or hexokinase (HexoK) (B). Data represent mean±SD of the relative migration compared with the control from 3 experiments performed in triplicate. The control (white bar) represents cell migration without nucleotide addition in lower chambers. *P<0.05 vs UDP alone; #P<0.05 vs UTP alone.

Conversely, to evaluate the potential involvement of P2Y₆ receptor in UDP-induced ASMC migration, we added hexokinase to the culture medium to avoid UTP contamination or formation as previously described.¹¹ Figure 3B shows that the chemotactic activity of UDP was maintained in the absence of UTP, destroyed by hexokinase treatment, suggesting that the P2Y₆ receptor was also involved in ASMC migration.

ATP, but not ADP, also demonstrated a chemotactic activity (Figure 4), suggesting that ATP-induced ASMC migration was not due to P2Y₁ activation but rather to the activation of other receptor(s), ie, the P2Y₂ or P2Y₄ receptors. However, the ability of ATP to induce ASMC migration was lower than that of UTP while an equipotent response was expected. This difference could be due to the efficient catabolism of ATP by ASMCs in culture. To verify this hypothesis, ,ß-methylene-ATP was added to ATP to protect it from ectonucleotidases.¹² Figure 4 shows that ,ß-methylene-ATP strongly increased the ATP-induced migration while inducing only a small nonsignificant response by itself. Because agonists could not discriminate P2Y₂ and P2Y₄ rat receptors, we used suramin, a P2Y₂ but not P2Y₄ receptor antagonist in the rat¹³ on UTP-induced ASMC migration. Figure 4B shows that suramin inhibited the UTP-induced migration dose dependently. This result is consistent with a major role of P2Y₂ receptor in this process.

View larger version (18K): [in this window] [in a new window]   Figure 4. Role of P2Y1 and P2Y4 receptors in UTP-induced ASMC migration. A, ASMC migration was evaluated after a 6-hour incubation with UTP or ATP 1 µmol/L in the presence or absence of ,ß-methylene-ATP 10 µmol/L. B, Cells were preincubated with suramin at indicated concentrations 10 minutes before loading in the upper chamber and submitted to the 6-hour migration test in the presence or absence of 10 µmol/L UTP. Data represent mean±SD of the relative migration compared with the control from 3 experiments performed in triplicate. The control (white bar) represents cell migration without nucleotide addition in lower chambers. *P<0.05 vs control; #P<0.05 vs ATP alone; and $P<0.05 vs UTP alone.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In previous experiments, we demonstrated that extracellular UTP is able to induce migration of cultured rat ASMCs in a dose-dependent manner.⁷ In the present work, we demonstrate that UDP can also induce ASMC migration. Because UTP and UDP can activate different P2Y receptors, the aim was to define the role of P2Y₂, P2Y₄, and P2Y₆ receptors in UTP-induced ASMC migration. First, we determined that the P2Y₂ receptor is 10- and 100-fold more highly expressed than P2Y₆ and P2Y₄ receptors, respectively. The expression of the P2Y₁ receptor was lower than that of the P2Y₄ receptor.

The very low level of P2Y₁ receptor mRNA was confirmed by the absence of ADP-induced migration of cultured ASMCs, demonstrating that P2Y₁ is not involved in this process.

Both UTP and UDP induced ASMC migration. The reversible conversion of UTP to UDP made it difficult to determine the P2Y receptor(s) involved in the UTP-induced migratory response. We found that a commercial solution of UDP and hexokinase-treated UDP solution (UTP-free) induced ASMC migration equally, thereby demonstrating that UDP is chemotactic by itself for ASMCs and that P2Y₆ receptor is thus able to mediate migration. Conversely, the migration experiment done in conditions limiting UTP degradation by NDPK treatment demonstrated the involvement of P2Y₂ and/or P2Y₄ receptor(s). The lower migration induced by UDP than by UTP could be the result of reduced receptor efficiency in this process, but it also could be due to the reduced P2Y₆ receptor expression as suggested by the smaller amount of P2Y₆ than P2Y₂ receptor mRNA found in cultured ASMCs.

ATP and UTP have been found to have an equal effect on the calcium fluxes resulting from stimulation of rat P2Y₂ and P2Y₄ receptors in transfected cells.^14,15 In the present study, ATP demonstrated a migratory effect lower than UTP. However, this difference decreased and became nonsignificant when ATP was protected from ectonucleotidase degradation by ,ß-methylene-ATP. This result suggests that the lower effect of ATP alone is certainly related to the ATP conversion in its catabolites. Although agonist-induced experiments could not allow the discrimination between P2Y₂- and P2Y₄-mediated response, the inhibitory effect of the rat P2Y₂ receptor antagonist, suramin,¹³ on UTP-induced migration and the fact that P2Y₂ mRNA content is 100-fold higher than that of P2Y₄ strongly suggest a prominent involvement of the P2Y₂ receptor in UTP-induced rat ASMC migration.

Taken together, these results suggest that UTP-induced migration is mainly due to the P2Y₂ receptor. Moreover, this work also demonstrated for the first time a functional role of P2Y₆ in ASMCs and that this receptor could be involved in UTP-mediated ASMC migration after UTP conversion in UDP.

The findings that P2Y₂ receptor is overexpressed in experimentally induced arterial intimal thickening⁸ and that UTP induces significant ASMC migration at concentrations as low as 10 nmol/L⁷ close to in vivo concentration³ suggest that UTP could play a significant role in pathophysiological conditions by inducing ASMC migration.

	Acknowledgments

 
This study was supported by grants from Institut National de la Santé et de la Recherche Médicale, Etablissement Public Régional No. 970301302, Fondation de France, and by a fellowship from Ministère de la Recherche et de la Technologie (H. Chaulet).

Received December 27, 2001; accepted February 12, 2002.

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/678    most recent 01.RES.0000013700.98464.8Ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pillois, X. Articles by Gadeau, A.-P. Search for Related Content PubMed PubMed Citation Articles by Pillois, X. Articles by Gadeau, A.-P. Related Collections Cell signalling/signal transduction Growth factors/cytokines Mechanism of atherosclerosis/growth factors