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Circulation Research. 2004;95:579-586
Published online before print August 5, 2004, doi: 10.1161/01.RES.0000141428.53262.a4
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(Circulation Research. 2004;95:579.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Rho Kinase–Induced Nuclear Translocation of ERK1/ERK2 in Smooth Muscle Cell Mitogenesis Caused by Serotonin

Yinglin Liu, Yuichiro J. Suzuki, Regina M. Day, Barry L. Fanburg

From the Tufts-New England Medical Center, Pulmonary, Critical Care and Sleep Division, Tupper Research Institute, Boston, Mass.

Correspondence to Barry L. Fanburg, MD, Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, 750 Washington St, #257, Boston, MA 02111. E-mail bfanburg{at}tufts-nemc.org


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
There is now considerable evidence supporting a mitogenic action of serotonin (5-HT) on vascular smooth muscle cells (SMC) that might participate in pulmonary hypertension (PH). Our previous studies have demonstrated that 5-HT–induced proliferation depends on the generation of reactive oxygen species and activation of extracellular signal-regulated kinase (ERK) 1/ERK2. Activation of Rho kinase (ROCK) in SMC also may be important in PH. We undertook the present study to assess the role of Rho A/ROCK and its possible relation to ERK1/ERK2 in 5-HT–induced pulmonary artery SMC proliferation. We found that this stimulation of SMC proliferation requires Rho A/ROCK as inhibition with Y27632, a ROCK inhibitor, or dominant negative (DN) mutant Rho A blocks 5-HT–induced proliferation, cyclin D1 expression, phosphorylation of Elk, and the DNA binding of transcription factors, Egr-1 and GATA-4. 5-HT activated ROCK, and the activation was blocked by GR 55562 and GR127935, 5-HT 1B/1D receptor antagonists, but not by serotonin transport (SERT) inhibitors. Activation of Rho kinase by 5-HT was independent of activation of ERK1/ERK2, and 5-HT activated ERK1/ERK2 independently of ROCK. Treatment of SMC with Y27632 and expression of DNRho A in cells blocked translocation of ERK1/ERK2 to the cellular nucleus. Depolymerization of actin with cytochalasin D (CD) and latrunculin B (latB) failed to block the translocation of ERK, suggesting that the actin cytoskeleton does not participate in the translocation. The studies show for the first time to our knowledge combinational action of SERT and a 5-HT receptor in SMC growth and Rho A/ROCK participation in 5-HT receptor 1B/1D-mediated mitogenesis of vascular SMCs through an effect on cytoplasmic to nuclear translocation of ERK1/ERK2.


Key Words: smooth muscle cells • serotonin • Rho kinase • ERK1/ERK2 • pulmonary hypertension


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
In addition to its actions as a vasoconstrictor and neurotransmitter, serotonin (5-HT) is now recognized to be a cellular mitogen.1–3 There is evidence that this mitogenic action is initiated by active transport via a cell surface transporter (SERT) of bovine, rat, and human pulmonary vascular smooth muscle cells (SMC).1,4–6 For other cells, the mitogenic action might be started through 1 or more of the cell surface receptors for 5-HT. A hierarchy of cell signaling responses occurs subsequent to ligation of the cell surface transporter or receptor. It has been well-established that these signaling responses include sequential activations of the small GTPase coupled protein, Rac-1, NADPH oxidase producing superoxide that is dismutated to H2O2, and extracellular signal-regulated kinase (ERK) 1/ERK2 MAP kinase.2,7–9

The small GTPase Rho A and its effector, Rho kinase (ROCK), also participate in cellular stress fiber formation and cell cycle progression.10–19 There has been limited study of the relationship of Rho A and ROCK to 5-HT. One study showed that Rho A bound to GTP is elevated in the rabbit aortic vascular ring preparation treated with 5-HT.20 Another study suggested the activation of Rho A and ROCK in 5-HT–induced contraction of the bovine middle cerebral artery.21 Serotonin participates in pulmonary hypertension,5,22,23 and a polymorphism of the 5-HT transporter has been proposed to be involved in pulmonary hypertension in humans.24 Because agents that block ROCK are currently available25,26 and may be useful in pulmonary hypertension,27–29 we have undertaken an investigation of the potential participation of ROCK in pulmonary arterial SMC signaling and proliferation produced by 5-HT. The results of our study show that ROCK is activated by 5-HT and that its activation is essential for SMC proliferation produced by 5-HT. Furthermore, with the use of a chemical inhibitor of ROCK and a dominant negative mutant of Rho A, we found that neither the activation of ROCK nor that of ERK1/ERK2 by 5-HT is dependent on the other, but rather both pathways are required to produce cellular proliferation. Both upregulate cyclin D1, activate Elk, and cause DNA binding of Egr-1 and GATA-4, transcription factors that participate in the mitogenic action of 5-HT on SMC. ROCK activation appears to depend on ligation of 5-HT 1B/1D rather than SERT. Importantly, ROCK participates in proliferation by causing translocation of activated ERK1/ERK2 to the cellular nucleus. To our knowledge, this is the first demonstration that the translocation of ERK to the nucleus is dependent on ROCK for any mitogenic event.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
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 down arrowDiscussion
 down arrowReferences
 
SMCs from bovine pulmonary artery were cultured in RPMI-1640 medium containing 10% fetal bovine serum and antibiotics. Thymidine uptake was determined with growth-arrested SMC treated with 1 µmol/L 5-HT, and supernatants of cell lysates were obtained for analysis. DN Rho A cDNA gene insertion was performed with adenoviral infections. Expressions of cyclin D1, Rho A, Erg-1, ERK, p-ERK, p-Elk, p MYPT1, and MYPT1 were analyzed with Western blots. Electrophoretic mobility shift assays were used to assess Egr-1 and GATA4. Immunochemistry was performed to localize intracellular ERK. F-actin stress fibers were visualized with a Zeiss fluorescent microscopy. Specific details regarding methodology and sources of materials used can be found in the online data supplement available at http://circres.ahajournals.org.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
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5-HT Activates ROCK
We examined the effects of 5-HT on MYPT1, a myosin phosphatase binding subunit, which is inactivated by phosphorylation by ROCK.25,30–32 As shown in Figure 1A, 5-HT (1 µmol/L) caused a transient phosphorylation of MYPT1, with a peak in 10 to 15 minutes. The effect of lysophosphosphatidic acid, a known activator of ROCK, is shown for comparison.33–35 Inactivation of MYPT1 by 5-HT was inhibited by the ROCK inhibitor, Y27632, in a dose-dependent manner (Figure 1B). Bovine pulmonary artery SMC contain both SERT and a variety of 5-HT receptors, including the 5-HT1B/1D receptor as determined by polymerase chain reaction (unpublished data). We examined the influence of SERT and 5-HT receptor inhibitors on ROCK activity. Although inhibition of SERT had no influence on ROCK activation, GR55562 and GR127935, known 5-HT1B/1D receptor antagonists, blocked activation of ROCK by 5-HT (online Figure IA, IB), and indicated that ROCK activation by 5-HT occurred via action on this receptor as opposed to SERT.



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  		Figure 1. Stimulation of Rho kinase (ROCK) activity by 5-HT. A, Activation by 5-HT of ROCK in growth-arrested bovine pulmonary arterial smooth muscle cells. B, Inhibition of ROCK activity by ROCK inhibitor Y27632. Phosphorylation of MYPT1 (Thr696) was determined by Western blot analysis using a phospho-specific antibody. **Significant difference from the untreated control value at P<0.05. *Significant difference from 5-HT alone control value P<0.05.

Role of ROCK in 5-HT–Induced Cell Growth
Treatment of cells with 5-HT caused an increase in thymidine incorporation that was inhibited in a dose-dependent manner by ROCK inhibitor Y27632 (Figure 2A). Similarly, 5-HT–mediated cyclin D1 expression was inhibited by pretreatment of cells with Y27632 (Figure 2B) and dominant negative Rho A (Figure 2C).



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  		Figure 2. 5-HT–induced smooth muscle cell proliferation and cyclin D1 expression are Rho A/ROCK-dependent. A, smooth muscle cells (SMC) were pretreated with Y27632 for 30 minutes and then incubated with 1 µmol/L 5-HT for 24 hours. DNA synthesis was determined by monitoring [3H]thymidine incorporation (n=8). B, Growth-arrested SMC were preincubated with 20 µmol/L Y27632 for 30 minutes. C, Infected with DNRhoA (10 pfu/live cell) for 48 hours, then treated with 1 µmol/L 5-HT for 6 hours. The expression of cyclin D1 was determined by Western blot analysis of the whole cell lysate. **Significant difference from the untreated control value at P<0.05. *Significant difference from 5-HT alone control value P<0.05.

To further determine the role of ROCK in cell growth signaling mediated by 5-HT, we examined the effects of Y27632 on the activation of transcription factors that control cell mitogenesis. The E twenty-six domain transcription factor Elk-1 is a direct target of the MAP kinase pathway.36 Phosphorylation of the Elk-1 transcriptional activation domain by MAP kinases triggers its activation.37–39 Elk participates in responses to ERK1/ERK2 in cellular proliferation.40 We found that treatment with 5-HT caused phosphorylation of Elk-1 of SMC (online Figure IIA) and that the activation is inhibited by Y27632 and U0126, inhibitors of ROCK and MEK, respectively (online Figure IIB).

Egr-1 is a well-known immediate early response gene, which has been shown to regulate cellular proliferation in response to various growth factors.41–43 We found that treatment of SMC with 5-HT–induced transient Egr-1 activation as monitored by electrophoretic mobility shift assays (online Figure IIC). The Egr-1 activation by 5-HT requires the activation of both ERK and ROCK, because the induction of Egr-1 activity was blocked by pretreatment of cells with Y27632 or U0126 (online Figure IID).

We recently reported that transcription factor GATA-4, another of the downstream effectors of ERK, plays a critical role in 5-HT signaling for SMC mitogenesis.44 Thus, we examined the effect of Y27632 on GATA-4 activity. We found that although Y27632 had no effect on basal levels of GATA-4 activity, this ROCK inhibitor blocked 5-HT–induced upregulation of GATA-4 (online Figure IIE). Taken together, these results indicate that the Rho A/ROCK pathway plays a role in mitogenic signaling induced by 5-HT in pulmonary artery SMC.

Interactions Between ERK and ROCK Pathways
ERK has been shown to play an important role in 5-HT–induced mitogenesis of SMC.1,7 As noted, inhibition of ROCK diminished both cell proliferation and ERK-dependent transcription factor activation induced by 5-HT in SMC. We therefore examined the effect of the ROCK/Rho A inhibitor Y27632 on 5-HT–induced ERK activation. Treatment of cells with 5-HT caused transient phosphorylation of ERK1/2 (online Figure IIIA). This increase in ERK phosphorylation by 5-HT (Figure 3A, lane 3) was not influenced by Y27632 (lane 4), whereas U0126, a MEK inhibitor, completely inhibited the activation (lane 12). Similarly, 5-HT–induced ERK activation was not influenced by an adenovirus expressing DNRho A (lane 8). These results indicate that the Rho A/ROCK pathway is not upstream of the MEK/ERK pathway in the 5-HT–induced signal transduction. Densitometry of these results with and without 5-HT is shown in Figure 3B.



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  		Figure 3. Activation of ERK1/ERK2 by 5-HT is independent of ROCK activation. A, SMC were preincubated with 20 µmol/L Y27632 or 10 µmol/L U0126 for 30 minutes, or infected with 10 pfu/live cell DNRho A for 48 hours, then treated with 1 µmol/L 5-HT for 5 minutes. Phosphorylation of ERK was determined by Western blot analysis of the whole cell lysate using the phospho-specific antibody. B, Densitometry measurements are for the 44-kDa band. Bar graphs represent mean and vertical bars represent the SD for n=4.

To determine whether the MEK/ERK pathway might be upstream to ROCK activation, we examined the effect of U0126 on ROCK activation. U0126 effectively inhibited 5-HT–induced thymidine incorporation and upregulated cyclin D1 expression (online Figure IIIB, IIIC). However, as shown in Figures 4 and 5, phosphorylation of MYPT1, a ROCK target (lane 2), was not influenced by U0126 (lane 5).



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  		Figure 4. 5-HT activation of ROCK does not require activation of ERK1/ERK2. SMC were pretreated with 10 µmol/L U0126 for 30 minutes, vehicle control groups were pretreated with 0.1% DMSO, and then SMC were stimulated with 1 µmol/L 5-HT for 15 minutes. The phosphorylation of MYPT1 (Thr696) was determined by Western blot with whole cell lysates. **Significant difference from the untreated control value at P<0.05.



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  		Figure 5. Effect of Rho A/ROCK on 5-HT-induced translocation of ERK1/2 into nucleus. Western blot of nuclear ERK in 5-HT–induced ERK translocation. A, Growth-arrested SMC were stimulated with 1 µmol/L 5-HT for the indicated time course. B, SMC were pretreated with 20 mol/L Y27632 or 10 µmol/L U0126 for 30 minutes, respectively, then incubated with 1 µmol/L 5-HT for 5 minutes. The level of ERK1/2 in the nucleus was determined by Western blot analysis using the ERK antibody in the cellular nuclear extracts. ERK translocation induced by 5-HT was detected by immunohistochemistry staining in SMC. C, SMC were treated with 5-HT for the indicated time course. D, Cells were pretreated with 10 µmol//L U 0126 or 20 µmol/ Y27632 for 30 minutes, or infected with DNRho A for 48 hours, then stimulated with 5-HT for 5 minutes. Localization of ERK protein was visualized using ERK antibody and subsequent staining with FITC-conjugated goat antirabbit IgG antibody. **Significant difference from the untreated control value at P<0.05. *Significant difference from 5-HT alone control value P<0.05.

Thus, although both the MEK/ERK and Rho A/ROCK pathways are essential for 5-HT–induced proliferation of SMC, Rho A/ROCK does not participate in the phosphorylation and activation of MEK/ERK and MEK/ERK does not activate Rho A/ROCK.

ROCK Regulates ERK Translocation to the Nucleus
Activation of ERK occurs in the cytoplasm, but to exert many of its actions ERK must translocate into the nucleus. ERK has been shown to activate various transcription factors by translocating to the nucleus after being phosphorylated and activated in the cytosol.45,46 To further determine the signaling role of Rho A/ROCK in 5-HT–induced mitogenesis of SMC, we examined the effect of Y27632 on nuclear translocation of ERK induced by 5-HT. Treatment of SMC with 5-HT increased nuclear translocation of ERK as determined by Western blot analysis of nuclear-rich cellular fractions. As shown in Figure 5A, ERK nuclear translocation occurred transiently with a peak at 5 minutes, consistent with its phosphorylation. This induction of ERK nuclear translocation by 5-HT was completely abrogated by pretreatment of cells with Y27632 (Figure 5B). U0126, which blocks ERK activation, also caused a similar inhibition of the translocation to the nucleus.

To confirm the experiments using nuclear-rich fractions, we performed immunohistochemistry using ERK antibody to directly visualize the ERK nuclear translocation. As shown in Figure 5C, in untreated cells, much of the ERK signal was dispersed in the cytosolic space around the nucleus. Treatment of cells with 5-HT caused the ERK protein to move into the nucleus. This could be visualized as early as after 2 minutes of 5-HT treatment, persisted for 10 to 20 minutes, and completely ceased by 40 minutes. Almost all of the cells, which were treated with 5-HT for 5 minutes, showed that ERK translocated to the nucleus (Figure 5C, third panel; Figure 5D, second panel). This dramatic translocation of ERK by 5-HT was not observed when cells were pretreated with U0126, DNRho A, or Y27632 (Figure 5D). These results demonstrate that ROCK regulates nuclear translocation of ERK in the 5-HT signaling mechanism for SMC mitogenesis.

To assess a possible role of the cellular cytoskeleton in the translocation of ERK1/ERK2 from the cytoplasm to the nucleus under the regulation of ROCK, we examined the 5-HT–induced translocation in the presence of cytochalasin D and latrunculin B, agents that depolymerize actin. Both cytochalasin D and latrunculin B blocked cellular proliferation but failed to influence ERK phosphorylation (online Figure IVA, IVB) or translocation of ERK1/ERK2 to the cellular nucleus (online Figure IVC).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Serotonin produces pulmonary vascular SMC proliferation in culture.2,3,6 Although some studies implicate actions on 5-HT receptors in the proliferative process,47–50 others support a hypothesis that the mitogenic action of 5-HT on vascular SMC is associated with the 5-HT transporter (SERT).1 We have performed extensive work demonstrating the participation of SERT in 5-HT–induced proliferation of bovine pulmonary artery SMC.2,3,8,9 5-HT activates a NADPH oxidase to produce superoxide that rapidly dismutates to H2O2. This H2O2 is responsible for activating the MAP kinase, ERK1/ERK2.7,8 Although the precise mechanism by which this occurs is not known, it may involve oxidation and inactivation of a relevant MAPK phosphatase.51–53 Activation of ERK is responsible for downstream actions that increase DNA binding of transcription factors, such as GATA-4,44 Egr-1, and Elk-1, and enhance expression of factors important in cell cycling, such as cyclin D1. SERT is important in the production of hypoxia-induced pulmonary hypertension in experimental animals4,54,55 and may participate in various forms of pulmonary hypertension in humans.24

Rho A is a member of the Ras superfamily of GTP-binding proteins. It cycles between a GDP-bound inactive state and a GTP-bound active state, and has been found to participate in cell growth, cell transformation, and change in shape and actin organization.11,13–15,56–59 The best-known downstream effector of Rho A in SMC is ROCK. ROCK phosphorylates a 130-kDa myosin phosphatase targeting (MYPT) subunit, also known as myosin binding subunit (MBS), and concurrently inactivates a phosphatase.60,27 Rho A/ROCK has been implicated in hypoxia-induced and monocrotaline-induced pulmonary hypertension in experimental animal models.28,29,61 Rho A and ROCK have been studied in platelet-derived growth factor-BB–induced proliferation of systemic vascular SMC.62 Despite the recognition that Rho A/Rho kinase participates in pulmonary hypertension, its role in SMC signaling processes that may contribute to the hypertension (such as SMC proliferation produced by 5-HT) has never been examined.

We have found that SMC proliferation, cyclin D1 expression, Elk activation, and DNA binding of the transcription factors, GATA-4 and Egr-1, are all dependent on activation of ROCK by 5-HT. Activation of ERK1/ERK2 MAPK by 5-HT is independent of activation of ROCK and, conversely, activation of ROCK by 5-HT is independent of activation of ERK1/ERK2. Of interest, our studies with SERT and 5-HT receptor inhibitors indicate that 5-HT 1B/1D receptors, but not SERT, may be responsible for the activation of ROCK by 5-HT. These observations raise the interesting question of whether SERT and a 5-HT receptor produce a combinatorial action in response to 5-HT to result in a mitogenic effect. This hypothesis is consistent with a requirement of the 5-HT1B receptor for development of hypoxia-induced pulmonary hypertension63 and recent studies suggesting interactions between SERT and 5-HT receptors.64

We initiated an examination of mechanisms by which Rho A/Rho kinase participates in the proliferative process produced by 5-HT. Although it has been recognized that growth factors promote rapid nuclear translocation of ERK1/ERK2,46,65 and that cellular actions of MAPK on gene regulation require its entry into the nucleus, little is known about the specific process by which this occurs. We have found that translocation of ERK1/ERK2 to the nucleus with 5-HT stimulation requires the action of Rho A/Rho kinase, although its activation does not. ROCK is known to participate in cell adhesion and assembly of cellular stress fibers,66 whereby altered nucleocytoplasmic trafficking of signaling molecules may occur.67 Furthermore, a recent report showed that cellular stretch and actin cytoskeleton configuration participate in ERK translocation via Rho A activation in cellular caveolae.68 Therefore, we undertook experimentation to determine whether the actin cytoskeleton might participate in the translocation of ERK we have observed. Although disruption of the cytoskeleton with cytochalasin D and latrunculin B blocked 5-HT–induced cell proliferation, ERK phosphorylation and translocation of ERK was unaffected by this treatment, indicating that translocation of ERK in our cells does not depend on an intact actin cytoskeleton.

Activation by 5-HT of the transcription factor Elk-1 is ROCK-dependent and ERK-dependent, providing supportive evidence that movement of ERK into the nucleus requires ROCK activation. As a direct target of the MAP kinase pathways, transcription factor Elk-1 is known to be coupled to ERK entry into the nucleus.69 Our studies show that in nuclei isolated from Y27632-pretreated SMC, the activating phosphorylation of Elk-1, which is catalyzed by ERK, was strikingly diminished (online Figure IIA, IIB) and correlated with a decrease in the abundance of activated ERK in the nuclei (Figure 5). In contrast, Y27632 did not alter phosphorylation of ERK in the total cell lysate. Our data suggest that impaired translocation of activated ERK to the nucleus by inhibition of ROCK is responsible for the decreased Elk-1 phosphorylation in SMC.

This is the first time to our knowledge that nuclear translocation of ERK has been reported to depend on Rho A/Rho kinase for 5-HT. There has been a report suggesting that ROCK-mediated signaling may be involved in ERK-mediated p21Cip/waf1 induction in PMA-induced proapoptotic TF-1 and D2 cells.70 However, unlike the results of our studies, they report that upregulated ROCK signal interfered with nuclear translocation of ERK. The process we observed may be similar to that reported for cellular cytoplasm to nucleus translocation of serum response factor produced by exposure of tracheal SMC to serum,71 which also requires Rho A/ROCK for the translocation. Also, it has been proposed previously that apoprotein D inhibits platelet-derived growth factor-BB–induced vascular SMC proliferation by prevention of phosphorylated ERK1/ERK2 movement to the nucleus.72

From these studies, we hypothesize that Rho A and ROCK play an important role in SMC proliferation produced by 5-HT through an influence on translocation of ERK1/ERK2 to the cellular nucleus. A diagram showing this hypothesis is presented in Figure 6. A polymerized actin cytoskeleton does not appear to participate in this translocation. The activation of ROCK by 5-HT is initiated through a 5-HT1B/1D receptor, suggesting a concerted action of SERT and 5-HT receptor(s) in cellular proliferation that is in need of further investigation.



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  		Figure 6. 5-HT–induced pulmonary vascular SMC proliferation requires cooperation between ERK and ROCK pathways. ERK activation occurs through 5-HT uptake by 5-HT transporter and subsequent NADPH oxidase activation by which increased superoxide anions stimulate ERK phosphorylation. ROCK activation occurs through 5-HT1B/1D receptor activation. Activated ROCK facilitates phospho-ERK translocation into nucleus and subsequent activation of nuclear transcription factors and cyclin D1 expression. There also may be direct actions of the ROCK pathway on transcription factors.


*    Acknowledgments
 
This work was supported by NIH/NHLBI R01 grants HL32723 (B.L.F.), HL67340 (Y.J.S.), and HL72844 (Y.J.S.). R.M.D. is the recipient of an American Heart Association National Center Scientist Development Award.


*    Footnotes
 
Original received February 4, 2004; revision received July 7, 2004; accepted July 26, 2004.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol. 1997; 272: L795–L806.[Medline] [Order article via Infotrieve]
  2. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Regulation of serotonin-induced DNA synthesis of bovine pulmonary artery smooth muscle cells. Am J Physiol. 1994; 266: L53–L60.[Medline] [Order article via Infotrieve]
  3. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol. 1994; 266: L46–L52.[Medline] [Order article via Infotrieve]
  4. Eddahibi S, Fabre V, Boni C, Martres MP, Raffestin B, Hamon M, Adnot S. Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin. Circ Res. 1999; 84: 329–336.[Abstract/Free Full Text]
  5. Egermayer P, Town GI, Peacock AJ. Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension. Thorax. 1999; 54: 161–168.[Free Full Text]
  6. Lee SL, Wang WW, Moore BJ, Fanburg BL. Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture. Circ Res. 1991; 68: 1362–1368.[Abstract/Free Full Text]
  7. Lee SL, Simon AR, Wang WW, Fanburg BL. H2O2 signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2001; 281: L646–L652.[Abstract/Free Full Text]
  8. Lee SL, Wang WW, Finlay GA, Fanburg BL. Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion. Am J Physiol. 1999; 277: L282–L291.[Medline] [Order article via Infotrieve]
  9. Lee SL, Wang WW, Fanburg BL. Superoxide as an intermediate signal for serotonin-induced mitogenesis. Free Radic Biol Med. 1998; 24: 855–858.[CrossRef][Medline] [Order article via Infotrieve]
  10. Amano M, Fukata Y, Kaibuchi K. Regulation and functions of Rho-associated kinase. Exp Cell Res. 2000; 261: 44–51.[CrossRef][Medline] [Order article via Infotrieve]
  11. Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, Kaibuchi K. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science. 1997; 275: 1308–1311.[Abstract/Free Full Text]
  12. Hu W, Bellone CJ, Baldassare JJ. RhoA stimulates p27(Kip) degradation through its regulation of cyclin E/CDK2 activity. J Biol Chem. 1999; 274: 3396–3401.[Abstract/Free Full Text]
  13. Kaibuchi K, Kuroda S, Amano M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu Rev Biochem. 1999; 68: 459–486.[CrossRef][Medline] [Order article via Infotrieve]
  14. Katoh K, Kano Y, Amano M, Kaibuchi K, Fujiwara K. Stress fiber organization regulated by MLCK and Rho-kinase in cultured human fibroblasts. Am J Physiol Cell Physiol. 2001; 280: C1669–C1679.[Abstract/Free Full Text]
  15. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999; 285: 895–898.[Abstract/Free Full Text]
  16. Olson MF, Paterson HF, Marshall CJ. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature. 1998; 394: 295–299.[CrossRef][Medline] [Order article via Infotrieve]
  17. Olson MF, Ashworth A, Hall A. An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science. 1995; 269: 1270–1272.[Abstract/Free Full Text]
  18. Seasholtz TM, Zhang T, Morissette MR, Howes AL, Yang AH, Brown JH. Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats. Circ Res. 2001; 89: 488–495.[Abstract/Free Full Text]
  19. van N, Amerongen GP, van Hinsbergh VW. Cytoskeletal effects of rho-like small guanine nucleotide-binding proteins in the vascular system. Arterioscler Thromb Vasc Biol. 2001; 21: 300–311.[Abstract/Free Full Text]
  20. Sakurada S, Okamoto H, Takuwa N, Sugimoto N, Takuwa Y. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am J Physiol Cell Physiol. 2001; 281: C571–C578.[Abstract/Free Full Text]
  21. Nishikawa Y, Doi M, Koji T, Watanabe M, Kimura S, Kawasaki S, Ogawa A, Sasaki K. The role of rho and rho-dependent kinase in serotonin-induced contraction observed in bovine middle cerebral artery. Tohoku J Exp Med. 2003; 201: 239–249.[CrossRef][Medline] [Order article via Infotrieve]
  22. Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Letitpretz P, Poubeau P, Cerrina J, Duroux P, Drouet L. Increased plasma serotonin in primary pulmonary hypertension. Am J Med. 1995; 99: 245–254.
  23. Herve P, Drouet L, Dosquet C, Launay JM, Rain B, Simonneau G, Caen J, Duroux P. Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. Am J Med. 1990; 89: 117–120.[CrossRef][Medline] [Order article via Infotrieve]
  24. Rabinovitch M. Linking a serotonin transporter polymorphism to vascular smooth muscle proliferation in patients with primary pulmonary hypertension. J Clin Invest. 2001; 108: 1109–1111.[CrossRef][Medline] [Order article via Infotrieve]
  25. Fujisawa K, Fujita A, Ishizaki T, Saito Y, Narumiya S. Identification of the Rho-binding domain of p160ROCK, a Rho-associated coiled-coil containing protein kinase. J Biol Chem. 1996; 271: 23022–23028.[Abstract/Free Full Text]
  26. Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M, Narumiya S. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol. 2000; 57: 976–983.[Abstract/Free Full Text]
  27. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996; 273: 245–248.[Abstract]
  28. Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I, Oka M. Rho/Rho-kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol. 2003;[Epub ahead of print].
  29. Fagan KA, Oka M, Bauer NR, Gebb SA, Ivy DD, Morris KG, McMurtry IF. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol. 2004;[Epub ahead of print]
  30. Totsukawa G, Yamakita Y, Yamashiro S, Hosoya H, Hartshorne DJ, Matsumura F. Activation of myosin phosphatase targeting subunit by mitosis-specific phosphorylation. J Cell Biol. 2003; 144: 735–744.
  31. Chitaley K, Weber D, Webb RC. RhoA/Rho-kinase, vascular changes, and hypertension. Curr Hypertens Rep. 2001; 3: 139–144.[Medline] [Order article via Infotrieve]
  32. Sward K, Mita M, Wilson DP, Deng JT, Susnjar M, Walsh MP. The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction. Curr Hypertens Rep. 2003; 5: 66–72.[Medline] [Order article via Infotrieve]
  33. Hashimoto T, Nakano Y, Yamashita M, Fang YI, Ohata H, Momose K. Role of Rho-associated protein kinase and histamine in lysophosphatidic acid-induced airway hyperresponsiveness in guinea pigs. Jpn J Pharmacol. 2002; 88: 256–261.[CrossRef][Medline] [Order article via Infotrieve]
  34. Mori M, Tsushima H. Activation of Rho signaling contributes to lysophosphatidic acid-induced contraction of intact ileal smooth muscle of guinea-pig. Can J Physiol Pharmacol. 2000; 78: 729–736.[CrossRef][Medline] [Order article via Infotrieve]
  35. Schmitz U, Thommes K, Beier I, Vetter H. Lysophosphatidic acid stimulates p21-activated kinase in vascular smooth muscle cells. Biochem Biophys Res Commun. 2002; 291: 687–691.[CrossRef][Medline] [Order article via Infotrieve]
  36. Papavassiliou AG. The role of regulated phosphorylation in the biological activity of transcription factors SRF and Elk-1/SAP-1. Anticancer Res. 1994; 14: 1923–1926.[Medline] [Order article via Infotrieve]
  37. El-Dahr SS, Dipp S, Baricos WH. Bradykinin stimulates the ERK–>Elk-1–>Fos/AP-1 pathway in mesangial cells. Am J Physiol. 1998; 75 (3 Pt 2): F343–F352.
  38. Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J. 1995; 14: 951–962.[Medline] [Order article via Infotrieve]
  39. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S. The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci. 2000; 20: 4563–4572.[Abstract/Free Full Text]
  40. Orsini MJ, Krymskaya VP, Eszterhas AJ, Benovic JL, Panettieri RA, Penn RB. MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation. Am J Physiol. 1999; 277 (3Pt1): L479–L488.[Medline] [Order article via Infotrieve]
  41. Thiel G, Cibelli G. Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol. 2002; 193: 287–292.[CrossRef][Medline] [Order article via Infotrieve]
  42. Fahmy RG, Khachigian LM. Antisense Egr-1 RNA driven by the CMV promoter is an inhibitor of vascular smooth muscle cell proliferation and regrowth after injury. J Cell Biochem. 2002; 84: 575–582.[CrossRef][Medline] [Order article via Infotrieve]
  43. Santiago FS, Atkins DG, Khachigian LM. Vascular smooth muscle cell proliferation and regrowth after mechanical injury in vitro are Egr-1/NGFI-A-dependent. Am J Pathol. 1999; 155: 897–905.[Abstract/Free Full Text]
  44. Suzuki YJ, Day RM, Tan CC, Sandven TH, Liang Q, Molkentin JD, Fanburg BL. Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. J Biol Chem. 2003; 278: 17525–17531.[Abstract/Free Full Text]
  45. Nilsen J, Brinton RD. Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. Proc Natl Acad Sci U S A. 2003; 100: 10506–10511.[Abstract/Free Full Text]
  46. Pouyssegur J, Volmat V, Lenormand P. Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Biochem Pharmacol. 2002; 64: 755–763.[CrossRef][Medline] [Order article via Infotrieve]
  47. Ishizuka J, Beauchamp RD, Townsend CM Jr., Greeley GH Jr., Thompson JC. Receptor-mediated autocrine growth-stimulatory effect of 5-hydroxytryptamine on cultured human pancreatic carcinoid cells. J Cell Physiol. 1992; 150: 1–7.[CrossRef][Medline] [Order article via Infotrieve]
  48. Nemecek GM, Coughlin SR, Handley DA, Moskowitz MA. Stimulation of aortic smooth muscle cell mitogenesis by serotonin. Proc Natl Acad Sci U S A. 1986; 83: 674–678.[Abstract/Free Full Text]
  49. Pakala R, Willerson JT, Benedict CR. Mitogenic effect of serotonin on vascular endothelial cells. Circulation. 1995; 90: 1919–1926.
  50. Pitt BR, Weng W, Steve AR, Blakely RD, Reynolds I, Davies P. Serotonin increases DNA synthesis in rat proximal and distal pulmonary vascular smooth muscle cells in culture. Am J Physiol. 1994; 266: L178–L186.[Medline] [Order article via Infotrieve]
  51. Guyton KZ, Liu Y, Gorospe M, Xu Q, Holbrook NJ. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem. 1996; 271: 4138–4142.[Abstract/Free Full Text]
  52. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000; 279: L1005–L1028.[Abstract/Free Full Text]
  53. Kim HS, Song MC, Kwak IH, Park TJ, Lim IK. Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence. J Biol Chem. 2003; 278: 37497–37510.[Abstract/Free Full Text]
  54. Eddahibi S, Raffestin B, Pham I, Launay JM, Aegerter P, Sitbon M, Adnot S. Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol. 1997; 272: H1173–H1181.[Medline] [Order article via Infotrieve]
  55. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest. 2000; 105: 1555–1562.[Medline] [Order article via Infotrieve]
  56. Bar-Sagi D, Hall A. Ras and Rho GTPases: a family reunion. Cell. 2003; 103: 227–238.
  57. Danen EH, Sonneveld P, Sonnenberg A, Yamada KM. Dual stimulation of Ras/mitogen-activated protein kinase and RhoA by cell adhesion to fibronectin supports growth factor-stimulated cell cycle progression. J Cell Biol. 2000; 151: 1413–1422.[Abstract/Free Full Text]
  58. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997; 389: 990–994.[CrossRef][Medline] [Order article via Infotrieve]
  59. Weber JD, Hu W, Jefcoat SC Jr., Raben DM, Baldassare JJ. Ras-stimulated extracellular signal-related kinase 1 and Rho A activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27. J Biol Chem. 1997; 272: 32966–32971.[Abstract/Free Full Text]
  60. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem. 1996; 271: 20246–20249.[Abstract/Free Full Text]
  61. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshita A. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 2004; 94: 385–393.[Abstract/Free Full Text]
  62. Kamiyama M, Utsunomiya K, Taniguchi K, Yokota T, Kurata H, Tajima N, Kondo K. Contribution of Rho A and Rho kinase to platelet-derived growth factor-BB-induced proliferation of vascular smooth muscle cells. J Atheroscler Thromb. 2003; 10: 117–123.[Medline] [Order article via Infotrieve]
  63. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR. Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935. Circ Res. 2001; 89: 1231–1239.[Abstract/Free Full Text]
  64. MacLean MR, Herve P, Eddahibi S, Adnot S. 5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol. 2000; 131: 161–168.[CrossRef][Medline] [Order article via Infotrieve]
  65. Brunet A, Roux D, Lenormand P, Dowd S, Keyse S, Pouyssegur J. Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J. 1999; 18: 664–674.[CrossRef][Medline] [Order article via Infotrieve]
  66. Narumiya S, Ishizaki T, Watanabe N. Rho effectors and reorganization of actin cytoskeleton. FEBS Lett. 1997; 410: 68–72.[CrossRef][Medline] [Order article via Infotrieve]
  67. Aplin AE, Juliano RL. Regulation of nucleocytoplasmic trafficking by cell adhesion receptors and the cytoskeleton. J Cell Biol. 2001; 155: 187–191.[Abstract/Free Full Text]
  68. Kawamura S, Miyamoto S, Brown JH. Initiation and transduction of stretch-induced RhoA and Rac1 activation through caveolae: cytoskeletal regulation of ERK translocation. J Biol Chem. 2003; 278: 31111–31117.[Abstract/Free Full Text]
  69. Aplin AE, Stewart SA, Assoian RK, Juliano RL. Integrin-mediated adhesion regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol. 2001; 153: 273–282.[Abstract/Free Full Text]
  70. Lai JM, Wu S, Huang DY, Chang ZF. Cytosolic retention of phosphorylated extracellular signal-regulated kinase and a Rho-associated kinase-mediated signal impair expression of p21(Cip1/Waf1) in phorbol 12-myristate-13- acetate-induced apoptotic cells. Mol Cell Biol. 2002; 22: 7581–7592.[Abstract/Free Full Text]
  71. Liu HW, Halayko AJ, Fernandes DJ, Harmon GS, McCauley JA, Kocieniewski P, McConville J, Fu Y, Forsythe SM, Kogut P, Bellam S, Dowell M, Churchill J, Lesso H, Kassiri K, Mitchell RW, Hershenson MB, Camoretti-Mercado B, Solway J. The Rho A/Rho kinase pathway regulates nuclear localization of serum response factor. Am J Respir Cell Mol Biol. 2003; 29: 39–47.[Abstract/Free Full Text]
  72. Sarjeant JM, Lawrie A, Kinnear C, Yablonsky S, Leung W, Massaeli H, Prichett W, Veinot JP, Rassart E, Rabinovitch M. Apolipoprotein D inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferated by preventing translocation of phosphorylated extracellular signal regulated kinase 1/2 to the nucleus. Arterioscler Thromb Vasc Biol. 2003; 23: 2172–2177.[Abstract/Free Full Text]



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