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Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate
Journal of Pharmacological Sciences xxx (2016) 1e7
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Current perspective
Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate Takuji Machida*, Ryosuke Matamura, Kenji Iizuka, Masahiko Hirafuji Department of Pharmacological Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 February 2016 Received in revised form 25 May 2016 Accepted 26 May 2016 Available online xxx
Sphingosine 1-phosphate (S1P) plays important roles in cardiovascular pathophysiology. S1P1 and/or S1P3, rather than S1P2 receptors, seem to be predominantly expressed in vascular endothelial cells, while S1P2 and/or S1P3, rather than S1P1 receptors, seem to be predominantly expressed in vascular smooth muscle cells (VSMCs). S1P has multiple actions, such as proliferation, inhibition or stimulation of migration, and vasoconstriction or release of vasoactive mediators. S1P induces an increase of the intracellular Ca2þ concentration in many cell types, including VSMCs. Activation of S1P3 seems to play an important role in Ca2þ mobilization. S1P induces cyclooxygenase-2 expression in VSMCs via both S1P2 and S1P3 receptors. S1P2 receptor activation in VSMCs inhibits inducible nitric oxide synthase (iNOS) expression. At the local site of vascular injury, vasoactive mediators such as prostaglandins and NO produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. Therefore, selective S1P2 receptor antagonists may have the potential to be therapeutic agents, in view of their antagonism of iNOS inhibition by S1P. Further progress in studies of the precise mechanisms of S1P may provide useful knowledge for the development of new S1P-related drugs for the treatment of cardiovascular diseases. © 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Sphingosine 1-phosphate Vascular smooth muscle cells Intracellular Ca2þ concentration Cyclooxygenase-2 Inducible nitric oxide synthase
1. Introduction Sphingosine 1-phosphate (S1P) exposed on the vascular wall plays important roles in cardiovascular pathophysiology. In the vascular system, the major source of S1P is plasma, and S1P is stored abundantly in hematopoietic cells such as red blood cells and platelets, which lack the S1P-degrading enzyme S1P lyase (1e4). Vascular endothelium has also emerged as a major contributor of plasma S1P (5). S1P concentrations in human plasma have been found in the range of 200e1000 nM (6e9). S1P in plasma binds to albumin and lipoproteins, in particular to high-density lipoproteins (HDLs). As S1P is the most active lipid component of HDLs, it is responsible, at least in part, for many of the cardiovascular effects of HDLs, including their ability to modulate vascular tone, promote angiogenesis, inhibit/reverse atherosclerosis, and protect against ischemia/reperfusion injury (10).
* Corresponding author. Tel./fax: þ81 133 23 3892. E-mail address: [email protected] (T. Machida). Peer review under responsibility of Japanese Pharmacological Society.
Five S1P receptor subtypes (S1P1, S1P2, S1P3, S1P4, and S1P5) have been identified in a wide variety of cells. These receptors are coupled to multiple pertussis toxin (PTX)-sensitive and PTXinsensitive G proteins (11). In several species, S1P1 and/or S1P3 receptors, rather than the S1P2 receptor, seem to be predominantly expressed in vascular endothelial cells, while S1P2 and/or S1P3 receptors, rather than the S1P1 receptor, seem to be predominantly expressed in vascular smooth muscle cells (VSMCs) (12e18). The S1P1 receptor is coupled to Gi/o protein, while S1P2 and S1P3 receptors are coupled to Gq, Gi/o, G12/13 proteins. Through these signaling cascades, S1P has multiple actions such as proliferation, inhibition or stimulation of migration, and vasoconstriction or release of vasoactive mediators (18e20). Modulation of vascular tone by S1P was reviewed recently by Igarashi and Michel (21). Under physiological condition, the function of VSMCs is regulated by many factors such as vasoactive mediators, mechanical forces, and neural transmitters. However, at a local site of vascular injury, some of the vasoactive mediators produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. In this context, a large amount of S1P is released from activated
http://dx.doi.org/10.1016/j.jphs.2016.05.010 1347-8613/© 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
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S1P3 receptor antagonist developed by their laboratory, prevented the S1P-induced increase in [Ca2þ]i in human coronary arterial SMCs. Tanaka et al. (23) have suggested that the Ca2þ response of rat aortic myocytes to S1P progressively increases during culture and that the mechanism by which this facilitatory response occurs is associated with change of S1P3 receptor expression during culture. Activation of voltage-dependent Ca2þ channels, including Ltype Ca2þ channels, is considered to be mainly involved in this S1Pinduced increase of [Ca2þ]i. We also found that inhibition of phospholipase C (PLC) and Gi protein completely and partially inhibited the S1P-induced increase in [Ca2þ]i, respectively, in VSMCs in both the presence and absence of extracellular Ca2þ. The effects of these inhibitors were also found in rat HTC4 hepatoma cells transfected with the S1P3 receptor (26). Taken together, S1P3 receptor-mediated PLC activation and intracellular Ca2þ mobilization in VSMCs may only be mediated partially through Gi/o protein. PLC is also activated by Gq protein, but it seems not to be activated by G12/13 protein, because the Rho kinase inhibitor Y 27632 had no effect. It is reported that both extracellular and intracellular S1P can activate store-operated Ca2þ entry (SOCE) in VSMCs (22, 24, 27, 28). Hopson et al. (27) reported that S1P-induced Ca2þ entry was inhibited by several SOCE inhibitors in primary aortic VSMCs and
platelets into the plasma, and this S1P is considered to affect the functions of VSMCs directly and dramatically. In view of these backgrounds, we will focus on the roles of S1P on the cellular function and signaling pathways of VSMCs in this short review. 2. Intracellular calcium dynamics Intracellular Ca2þ concentration ([Ca2þ]i) in VSMCs plays a regulatory role as a second messenger in a variety of cellular functions. S1P induces an increase of [Ca2þ]i in many cell types, including VSMCs (22,23). Recent reports suggest that S1P3 activation plays an important role in Ca2þ mobilization. We reported that S1P induced a biphasic change in [Ca2þ]i, that is, a transient peak increase followed by smaller sustained increases in [Ca2þ]i in cultured rat aortic smooth muscle cells (SMCs) (24) (Fig. 1A). This elevation was initiated at a concentration of more than 0.001 mM, and a significant increase in both peak and sustained [Ca2þ]i was observed at more than 0.1 mM (Fig. 1B). We found that both extracellular Ca2þ influx and Ca2þ release from the sarcoplasmic reticulum have a role in peak elevation. Transfection of small interfering RNA (siRNA) targeting the S1P3 receptor significantly decreased both peak and sustained [Ca2þ]i (Fig. 1C). In addition, Murakami et al. (25) reported that TY-52156, which is a selective
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Fig. 1. S1P increases [Ca2þ]i in VSMCs via the S1P3 receptor in cultured rat VSMCs. A: A representative result. The cells were stimulated with S1P (1 mM). B: S1P concentrationdependent increase of [Ca2þ]i in VSMCs. The cells were stimulated with the indicated concentrations of S1P. Peak: peak [Ca2þ]i after stimulation; at 5 min: [Ca2þ]i after stimulation. C: Effect of S1P on [Ca2þ]i in VSMCs transfected with S1P receptor siRNA. The cells were stimulated with S1P. Basal: basal [Ca2þ]i before stimulation; peak: peak [Ca2þ]i after stimulation; at 5 min: [Ca2þ]i after stimulation. Symbols or bars show mean ± S.E.M. values of (n) experiments for B, n ¼ 10e11 experiments for C. When not visible, error bars are included in the symbol. *P < 0.01, **P < 0.001 vs. basal. yP < 0.001 vs. scrambled siRNA. Adopted from Ref. (23) with permission.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
T. Machida et al. / Journal of Pharmacological Sciences xxx (2016) 1e7
furthermore reported that S1P activated stromal interaction molecule 1 (STIM1). SOCE was observed in VSMCs that were without either S1P2 or S1P3 receptors, and intracellular S1P activated SOCE by STIM1 recruitment to the plasma membrane, strongly suggesting that not only extracellular but also intracellular S1P can activate SOCE. Furthermore, they showed that the S1Pinduced SOCE contributes to constriction of cerebral arteries. The role of intracellular S1P on SOCE will be further discussed in Section 5, which addresses the role of sphingosine kinase in VSMCs. Transient receptor potential canonical (TRPC) proteins are now believed to have an important role in not only SOCE but also receptoroperated Ca2þ entry (ROCE). In fact, S1P reportedly activates TRPC5 in human saphenous vein SMCs (22). TRPC5 is expressed in the SMCs of human veins together with TRPC1, which forms a complex with TRPC5, and S1P also activates TRPC5-TRPC1 heteromultimeric channels. Furthermore, we have found that S1P can cause not only SOCE but also ROCE in VSMCs (24), but the mechanisms of ROCE by S1P are still largely unknown. Further studies are required to clarify the detailed mechanisms. There is increasing evidence that the immune modulator FTY720, which is used as a treatment for multiple sclerosis, might also be applied to cardiovascular diseases such as atherosclerosis. FTY720 is phosphorylated by sphingosine kinase, and the phosphorylated compound is a potent agonist of S1P receptors, except S1P2. In fact, FTY720 phosphate (FTY720-P) induces an increase in [Ca2þ]i in Chinese hamster ovary (CHO) cells that stably express the S1P3 receptor (25). Moreover, various selective S1P receptor agonists have become commercially available. In addition to FTY720-P, they could be useful tools to elucidate further the physiological roles of S1P receptors in vascular cells. 3. Eicosanoid production Eicosanoids produced by cyclooxygenase (COX) in the vascular wall have important roles in cardiovascular pathophysiology. There are two isoforms of COX: COX-1 and COX-2. COX-1 is constitutively expressed in most cells, whereas COX-2 is induced in certain cell types including VSMCs. Recent studies have implicated a regulatory function of sphingolipids in prostanoid production (29). S1P reportedly induces COX-2 expression and subsequently produces prostanoids in many cells such as aortic SMCs (12, 18, 30), coronary artery SMCs (17), tracheal SMCs (31), renal mesangial cells (32), and human amnionderived WISH cells (33). In aortic SMCs, we reported that S1P (>1 mM) significantly induced prostaglandin I2 (PGI2) production (Fig. 2A), which is major arachidonic metabolite in rat aortic SMCs (18). S1P-induced COX-2, but not COX-1, expression in VSMCs. Both S1P2 and S1P3 receptors seem to mediate the induction of COX-2 by S1P. Previously, we showed that suramin, an S1P3 receptor antagonist, significantly inhibited S1P-induced COX-2 expression (Fig. 2B). In addition, we confirmed that the selective S1P2 receptor antagonist JTE-013 (10 mM) also significantly inhibited COX-2 expression (unpublished data). JTE-013 has been reported to inhibit the specific binding of radiolabeled S1P to membranes of CHO cells transfected with human and rat S1P2 receptors, with IC50 values of 17 ± 6 and 22 ± 9 nM, and has been reported to not affect S1P binding to S1P3 and S1P1 at concentrations up to 10 mM (34e36). In agreement with our results, both S1P2 and S1P3 receptors have been shown to be necessary for COX-2 induction in human aortic SMCs (12). In coronary artery SMCs, Damirin et al. (17) suggested that S1P-induced cAMP accumulation caused by PGI2 synthesis is mediated mainly by the S1P2 receptor, although they have not directly elucidated which S1P receptor subtype is responsible for COX-2 induction. It has been reported that S1P
3
activates nucleocytoplasmic shuttling of the mRNA-stabilizing protein HuR, which in turn stabilizes COX-2 mRNA and elicits COX-2 expression in macrophages (37). Thus, S1P presumably increases COX-2 expression by inducing transcription of COX-2 mRNA and by stabilization of its mRNA in VSMCs. Increased [Ca2þ]i by S1P has an important role in COX-2 induction, since S1P has no effect on COX-2 expression under extracellular and intracellular Ca2þ-depleted conditions and a protein kinase C (PKC) inhibitor inhibits COX-2 induction (18). This Ca2þdependent activation of PKC might be mediated by Gi and Gq, but not G12/13, protein-coupled S1P receptors. Inhibition of Gi protein by PTX partially inhibited COX-2 induction, while inhibition of Rho kinase, which is the main signaling molecule of G12/13 protein, failed to inhibit COX-2 induction. Growing evidence suggests that HDL-associated S1P has a role in the vascular protective effects of HDLs. In addition to their role in reverse cholesterol transport, HDLs also exert beneficial effects on anti-oxidative, anti-inflammatory, anti-thrombotic, and endothelium-dependent vasorelaxation (38,39). S1P is known as the most active lipid component of HDLs and plays a key role in vascular biology as an extracellular mediator (10). HDLs increase PGI2 synthesis in both VSMCs and endothelial cells through a mechanism involving COX-2 induction (12). Furthermore, both HDL- and S1P-induced COX-2 inductions are diminished by either S1P receptor antagonists (suramin, JTE-013, or VPC 23019) or transfection of S1P2 and S1P3 siRNA (12). COX-2-derived prostanoids are now believed to be key protective molecules for the cardiovascular system (40). Enhanced COX-2 induction in vascular walls is considered to function primarily as a defensive and compensatory mechanism for the lack of endothelial COX-1 function at the site of a local vascular injury associated with thrombosis, atherosclerosis, and hypertension. In addition to its vasodilating action, PGI2 has inhibitory effects on platelet aggregation and adhesion, leukocyte adhesion, and VSMC proliferation/migration (41). In fact, we reported that the production of PGI2 and interleukin-1b (IL-1b)-induced COX-2 protein expression were lower in VSMCs from spontaneously hypertensive rats-stroke prone (SHRSP) than from normotensive Wistar Kyoto rats (42). It is worthy to note that S1P-induced COX-2 expression in airway SMCs is also considered to have a protective effect against asthma, because of the enhancement of PGE2 production, which represses b2-adrenergic activity by receptor desensitization (43). As we discussed above, [Ca2þ]i elevation by S1P starts at a concentration of more than 0.001 mM, and a significant increase in both peak and sustained [Ca2þ]i was observed at more than 0.1 mM, while PGI2 release by S1P starts at a concentration of more than 0.1 mM. The nano-molar order of the S1P-induced increase in [Ca2þ]i may have a physiological role in VSMCs, but the excessive elevation of [Ca2þ]i by a micro-order of S1P may cause abnormal vasoconstriction. The PGI2 released by S1P may have a role in the amelioration of the abnormal situation via autocrine and/or paracrine action.
4. Nitric oxide production Nitric oxide (NO) produced by NO synthase (NOS) in the vascular wall plays important roles in cardiovascular pathophysiology. In addition to its vasodilating action, NO has inhibitory effects on platelet aggregation and adhesion, leukocyte adhesion, and VSMC proliferation/migration (44). There are three isoforms of NOS: neuronal NOS, inducible NOS (iNOS), and endothelial NOS (eNOS). eNOS is restricted to the endothelium, while iNOS is expressed in several cell types including VSMCs following stimulation with cytokines such as IL-1b.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
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Fig. 2. S1P induces PGI2 production and COX-2 expression in cultured rat VSMCs. A: PGI2 production was determined by radioimmunoassay. The cells were treated with various concentrations of S1P for 24 h. B: S1P induces COX-2 expression via S1P3 receptor. COX-2 protein expression was determined by western blotting. The cells were pretreated with or without suramin (100 mM) for 1 h and then treated with or without S1P (1 mM) for 4 h. Upper: A representative image. Lower: Densitometric analysis expressed taking samples treated with S1P alone as 100%. Bars show mean ± S.E.M. values of 4 and 6 experiments for A and B, respectively. **P < 0.01, vs. control. ##P < 0.01 vs. S1P alone. Adopted from Ref. (18) with permission.
We reported that S1P (>0.1 mM) inhibited IL-1b-induced NO production and iNOS expression in VSMCs (19) (Fig. 3). This iNOS inhibition was inhibited partially by PTX (19) (Fig. 3). Since this effect of PTX disappeared under the Ca2þ-depleted condition, S1P-induced iNOS inhibition was mediated partially by Ca2þdependent Gi protein coupled to the S1P receptor. Conversely, the Rho kinase inhibitor Y 27632 partially but significantly attenuated the inhibitory effect of S1P on iNOS expression in the Ca2þdepleted condition, but did not affect it in the presence of Ca2þ. S1P also significantly inhibited the IL-1b-induced persistent activation of extracellular signal-regulated kinase (ERK), which is necessary for IL-1b-induced iNOS expression, but had no effect in the Ca2þ-depleted condition. This ERK inhibition was probably mediated by Gq protein, because PTX did not affect this ERK inhibition. Taken together, we conclude that S1P inhibits IL-1binduced iNOS expression in rat VSMCs through multiple mechanisms involving both PTX-sensitive and -insensitive G proteins coupled to S1P receptors. Furthermore, Ca2þ-dependent ERK inhibition and Ca2þ-independent Rho kinase activation are involved in the inhibitory mechanism of iNOS inhibition. We have also observed that JTE-013 (10 mM) impaired the inhibitory effect of S1P on iNOS protein expression, suggesting that the S1P2 receptor at least has a role in S1P-induced iNOS inhibition (unpublished data). In agreement with our results, S1P inhibits
IL-1b-induced iNOS expression in rat mesangial cells and bovine/ human chondrocytes (45e47). Although signal transduction seems to be different between these cells, this iNOS inhibition is mediated by S1P2 receptor activation, since both JTE-013 and knockdown of the S1P2 receptor by transfection with S1P2 siRNA fully reversed IL-1b-induced iNOS expression in human chondrocytes (47). Counteraction of IL-1b-induced iNOS expression by S1P in chondrocytes from osteoarthritis patients may help to prevent chronic inflammation. However, since iNOS induction in VSMCs is also considered to function primarily as a defensive and compensatory mechanism for the lack of endothelial function at the site of a local vascular injury associated with thrombosis, atherosclerosis, and hypertension, S1P inhibition of NO production in VSMCs may be of relevance to local pathophysiological conditions. In fact, iNOS expression in VSMCs is negatively modulated by a variety of vasoactive mediators such as angiotensin II (48) and 5-hydroxytryptamine (49,50), which cause vessel contraction and VSMC proliferation. Furthermore, we reported that IL-1b-induced NO production and iNOS expression in VSMCs derived from SHRSP and under pressure stress, which simulates systolic hypertension, were lower than in control cells (19,42). Therefore, selective S1P2 receptor antagonists may be helpful therapeutically, in view of their antagonism of iNOS inhibition by S1P.
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Fig. 3. S1P inhibits IL-1b-induced NO production and iNOS expression in cultured rat VSMCs. The cells were untreated or pretreated with PTX (400 mg/ml) for 24 h. Cells were then stimulated with IL-1b for 24 h in the absence or presence of various concentrations of S1P. A: NO production in the culture medium was measured by NOx Autoanalyzer (ENO-10, Eicom, Kyoto, Japan). Amount of NO expressed as a percentage, taking samples treated with IL-1b alone as 100%. Bars show mean ± S.E.M. values of 4 experiments. **P < 0.01 vs. IL1b alone. B: A representative image of iNOS protein expression. The protein expression was determined by western blotting. b-Actin protein expression was also evaluated as a loading control. Adopted from Ref. (19) with permission.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
T. Machida et al. / Journal of Pharmacological Sciences xxx (2016) 1e7
NO signaling pathways (52). Although S1P negatively regulates iNOS expression in VSMCs as mentioned above, it is possible that the intracellular S1P generated by SphK1 affects iNOS expression via autocrine/paracrine signaling mechanisms in VSMCs. In fact, our preliminary experiments showed that DMS significantly potentiated IL-1b-induced iNOS expression and NO production in VSMCs (unpublished data).
5. Role of sphingosine kinase in VSMCs Recently, VSMCs have been shown to generate S1P intracellularly by sphingosine kinase (SphK) from sphingosine. Two isoforms of SphK have been identified: SphK1 and SphK2. Zhu et al. (51) reported that corticotrophin-releasing factor (CRF) accelerates S1P synthesis by inducing SphK1 expression in both A7r5 cells and rat primary VSMCs. They showed that the synthesized S1P is secreted and activates the S1P3 receptor. Since the SphK inhibitor dimethylsphingosine (DMS) and the S1P3 receptor antagonist CAY 10444 inhibit CRF-induced VSMCs migration, they concluded that S1P generation and S1P3 activation in VSMCs are responsible for CRF-induced migration. Wilson et al. (28) have reported that intracellular S1P generated by SphK1 has an important role in angiotensin II (Ang II)-induced SOCE in VSMCs, showing that Ang II activates SphK activity and increases intracellular S1P. They also found that Ang II induces biphasic Ca2þ entry, consisting of an immediate peak due to inositol tris-phosphate-dependent release of intracellular Ca2þ, followed by a sustained transmembrane Ca2þ influx through SOCE, and that inhibition of SphK1 attenuates the second phase of Ca2þ influx. Furthermore, they found that genetic deletion of SphK1 significantly inhibits both the acute hypertensive response to Ang II in anaesthetized SphK1 knockout mice and the sustained hypertensive response to continuous infusion of Ang II in conscious animals. This indicates that SphK1 in VSMCs plays a critical role in the development of Ang II-induced hypertension. In mouse BV2 microglial cells activated with lipopolysaccharide, DMS inhibits iNOS mRNA expression, suggesting that SphK1 regulates
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6. Clinical relevance Under normal physiological conditions, vasoactive agents derived from the endothelium and other tissues modulate endothelial cell and VSMC function to maintain vascular homeostasis, including vascular tone. Kerage et al. (53) have reported that physiologically low concentrations of S1P (ca. 0.1 mM) are thought to maintain the endothelial barrier, while pathophysiological concentrations of S1P (ca. 10 mM) disrupt the endothelial barrier and increase vascular permeability. This indicates that S1P itself at high concentrations, as well as other circulating vasoconstrictors, reaches VSMCs through endothelial leakage. The high concentration of S1P can cause an increase in [Ca2þ]i and induce PGI2 production in VSMCs via the S1P3 receptor as we mentioned above. S1P is known to play important roles in the pathogenesis of atherosclerosis. Although the S1P3 receptor has been reported to have some atheroprotective effects (12,54), the S1P2 receptor instead plays a critical role in the development of atherosclerosis. Twenty weeks of FTY720 treatment in apolipoprotein E deficient mice that were fed a high-cholesterol diet dramatically reduced
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NO production Fig. 4. Possible mechanisms of modulating VSMCs functions by S1P at a local site of vascular injury, such as atherosclerotic lesion. A: Role of S1P2 and S1P3 receptors in VSMCs. B: The concentration-dependent changes of VSMCs function by S1P.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
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atherosclerotic lesion volume, macrophage, and collagen content (55). Inhibition of the release of monocyte chemoattractant protein-1 (MCP-1) via S1P3 receptor by VSMCs is thought to be involved in the mechanisms. Wang et al. (56) have reported that S1P2 receptor was expressed in macrophages, endothelial cells, and SMCs in atherosclerotic aortas. In S1pr2/Apoe/ mice fed a highcholesterol diet, the area of atherosclerotic plaques was markedly decreased compared with S1pr2þ/þApoe/ mice. S1P2 receptor in monocytes/macrophages promotes atherosclerosis through mechanisms including the regulation of modified LDL accumulation, cytokine production, and cell migration. The activation of S1P2 receptors in endothelial cells inhibits eNOS activation and promotes proinflammatory cytokines such as MCP-1. In VSMCs, the activation of S1P2 receptor is assumed to destabilize plaques by decreasing the density of a-smooth muscle actin-positive SMCs, which is likely mediated through the inhibition of proliferation and SMC migration into the intima. As we mentioned above, S1P is known as the most active lipid component of HDL, an atheroprotective lipoprotein. Some atheroprotective effects of HDL such as eNOS activation were shown to be mediated via the S1P3 receptor (54). Thus, at local pathophysiological sites with endothelial dysfunction, iNOS inhibition by S1P2 receptor activation in VSMCs may further magnify the atherosclerosis. In this way, selective S1P2 receptor antagonists may be helpful therapeutically for cardiovascular diseases, by antagonizing of iNOS inhibition by S1P. 7. Conclusion As shown in Fig. 4A, at a local site of vascular injury, some vasoactive mediators such as prostaglandins and NO produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. A large amount of S1P is released from activated platelets into the plasma, and this S1P is considered to affect the functions of VSMCs directly and dramatically. More than 1 mM S1P significantly induces an increase in [Ca2þ]i via S1P3 receptor activation, while it significantly decreases IL-1b-induced NO production via S1P2 receptor activation. COX-2 induction by S1P stimulation is mediated by both S1P2 and S1P3 receptor activation (Fig. 4A). As discussed above, the excessive elevation of [Ca2þ]i and the inhibition of NO production by a micro-order of S1P may cause abnormal vasoconstriction. The PGI2 released by S1P may have a role in the amelioration of the abnormal situation via autocrine and/or paracrine action (Fig. 4B). Furthermore, selective S1P2 receptor antagonists may be helpful therapeutically for cardiovascular diseases, in view of their antagonism of iNOS inhibition by S1P. Further progress in studies for the precise cellular and molecular mechanisms of S1P may provide useful knowledge for the development of new S1P-related drugs for the treatment of cardiovascular diseases. Conflict of interest The authors declare no conflict of interest. References (1) Yatomi Y, Ozaki Y, Ohmori T, Igarashi Y. Sphingosine 1-phosphate: synthesis and release. Prostaglandins Other Lipid Mediat. 2001;64:107e122. (2) Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316:295e298. (3) Hla T, Venkataraman K, Michaud J. The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta. 2008;1781:477e482.
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Current perspective
Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate Takuji Machida*, Ryosuke Matamura, Kenji Iizuka, Masahiko Hirafuji Department of Pharmacological Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 February 2016 Received in revised form 25 May 2016 Accepted 26 May 2016 Available online xxx
Sphingosine 1-phosphate (S1P) plays important roles in cardiovascular pathophysiology. S1P1 and/or S1P3, rather than S1P2 receptors, seem to be predominantly expressed in vascular endothelial cells, while S1P2 and/or S1P3, rather than S1P1 receptors, seem to be predominantly expressed in vascular smooth muscle cells (VSMCs). S1P has multiple actions, such as proliferation, inhibition or stimulation of migration, and vasoconstriction or release of vasoactive mediators. S1P induces an increase of the intracellular Ca2þ concentration in many cell types, including VSMCs. Activation of S1P3 seems to play an important role in Ca2þ mobilization. S1P induces cyclooxygenase-2 expression in VSMCs via both S1P2 and S1P3 receptors. S1P2 receptor activation in VSMCs inhibits inducible nitric oxide synthase (iNOS) expression. At the local site of vascular injury, vasoactive mediators such as prostaglandins and NO produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. Therefore, selective S1P2 receptor antagonists may have the potential to be therapeutic agents, in view of their antagonism of iNOS inhibition by S1P. Further progress in studies of the precise mechanisms of S1P may provide useful knowledge for the development of new S1P-related drugs for the treatment of cardiovascular diseases. © 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Sphingosine 1-phosphate Vascular smooth muscle cells Intracellular Ca2þ concentration Cyclooxygenase-2 Inducible nitric oxide synthase
1. Introduction Sphingosine 1-phosphate (S1P) exposed on the vascular wall plays important roles in cardiovascular pathophysiology. In the vascular system, the major source of S1P is plasma, and S1P is stored abundantly in hematopoietic cells such as red blood cells and platelets, which lack the S1P-degrading enzyme S1P lyase (1e4). Vascular endothelium has also emerged as a major contributor of plasma S1P (5). S1P concentrations in human plasma have been found in the range of 200e1000 nM (6e9). S1P in plasma binds to albumin and lipoproteins, in particular to high-density lipoproteins (HDLs). As S1P is the most active lipid component of HDLs, it is responsible, at least in part, for many of the cardiovascular effects of HDLs, including their ability to modulate vascular tone, promote angiogenesis, inhibit/reverse atherosclerosis, and protect against ischemia/reperfusion injury (10).
* Corresponding author. Tel./fax: þ81 133 23 3892. E-mail address: [email protected] (T. Machida). Peer review under responsibility of Japanese Pharmacological Society.
Five S1P receptor subtypes (S1P1, S1P2, S1P3, S1P4, and S1P5) have been identified in a wide variety of cells. These receptors are coupled to multiple pertussis toxin (PTX)-sensitive and PTXinsensitive G proteins (11). In several species, S1P1 and/or S1P3 receptors, rather than the S1P2 receptor, seem to be predominantly expressed in vascular endothelial cells, while S1P2 and/or S1P3 receptors, rather than the S1P1 receptor, seem to be predominantly expressed in vascular smooth muscle cells (VSMCs) (12e18). The S1P1 receptor is coupled to Gi/o protein, while S1P2 and S1P3 receptors are coupled to Gq, Gi/o, G12/13 proteins. Through these signaling cascades, S1P has multiple actions such as proliferation, inhibition or stimulation of migration, and vasoconstriction or release of vasoactive mediators (18e20). Modulation of vascular tone by S1P was reviewed recently by Igarashi and Michel (21). Under physiological condition, the function of VSMCs is regulated by many factors such as vasoactive mediators, mechanical forces, and neural transmitters. However, at a local site of vascular injury, some of the vasoactive mediators produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. In this context, a large amount of S1P is released from activated
http://dx.doi.org/10.1016/j.jphs.2016.05.010 1347-8613/© 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
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S1P3 receptor antagonist developed by their laboratory, prevented the S1P-induced increase in [Ca2þ]i in human coronary arterial SMCs. Tanaka et al. (23) have suggested that the Ca2þ response of rat aortic myocytes to S1P progressively increases during culture and that the mechanism by which this facilitatory response occurs is associated with change of S1P3 receptor expression during culture. Activation of voltage-dependent Ca2þ channels, including Ltype Ca2þ channels, is considered to be mainly involved in this S1Pinduced increase of [Ca2þ]i. We also found that inhibition of phospholipase C (PLC) and Gi protein completely and partially inhibited the S1P-induced increase in [Ca2þ]i, respectively, in VSMCs in both the presence and absence of extracellular Ca2þ. The effects of these inhibitors were also found in rat HTC4 hepatoma cells transfected with the S1P3 receptor (26). Taken together, S1P3 receptor-mediated PLC activation and intracellular Ca2þ mobilization in VSMCs may only be mediated partially through Gi/o protein. PLC is also activated by Gq protein, but it seems not to be activated by G12/13 protein, because the Rho kinase inhibitor Y 27632 had no effect. It is reported that both extracellular and intracellular S1P can activate store-operated Ca2þ entry (SOCE) in VSMCs (22, 24, 27, 28). Hopson et al. (27) reported that S1P-induced Ca2þ entry was inhibited by several SOCE inhibitors in primary aortic VSMCs and
platelets into the plasma, and this S1P is considered to affect the functions of VSMCs directly and dramatically. In view of these backgrounds, we will focus on the roles of S1P on the cellular function and signaling pathways of VSMCs in this short review. 2. Intracellular calcium dynamics Intracellular Ca2þ concentration ([Ca2þ]i) in VSMCs plays a regulatory role as a second messenger in a variety of cellular functions. S1P induces an increase of [Ca2þ]i in many cell types, including VSMCs (22,23). Recent reports suggest that S1P3 activation plays an important role in Ca2þ mobilization. We reported that S1P induced a biphasic change in [Ca2þ]i, that is, a transient peak increase followed by smaller sustained increases in [Ca2þ]i in cultured rat aortic smooth muscle cells (SMCs) (24) (Fig. 1A). This elevation was initiated at a concentration of more than 0.001 mM, and a significant increase in both peak and sustained [Ca2þ]i was observed at more than 0.1 mM (Fig. 1B). We found that both extracellular Ca2þ influx and Ca2þ release from the sarcoplasmic reticulum have a role in peak elevation. Transfection of small interfering RNA (siRNA) targeting the S1P3 receptor significantly decreased both peak and sustained [Ca2þ]i (Fig. 1C). In addition, Murakami et al. (25) reported that TY-52156, which is a selective
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Fig. 1. S1P increases [Ca2þ]i in VSMCs via the S1P3 receptor in cultured rat VSMCs. A: A representative result. The cells were stimulated with S1P (1 mM). B: S1P concentrationdependent increase of [Ca2þ]i in VSMCs. The cells were stimulated with the indicated concentrations of S1P. Peak: peak [Ca2þ]i after stimulation; at 5 min: [Ca2þ]i after stimulation. C: Effect of S1P on [Ca2þ]i in VSMCs transfected with S1P receptor siRNA. The cells were stimulated with S1P. Basal: basal [Ca2þ]i before stimulation; peak: peak [Ca2þ]i after stimulation; at 5 min: [Ca2þ]i after stimulation. Symbols or bars show mean ± S.E.M. values of (n) experiments for B, n ¼ 10e11 experiments for C. When not visible, error bars are included in the symbol. *P < 0.01, **P < 0.001 vs. basal. yP < 0.001 vs. scrambled siRNA. Adopted from Ref. (23) with permission.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
T. Machida et al. / Journal of Pharmacological Sciences xxx (2016) 1e7
furthermore reported that S1P activated stromal interaction molecule 1 (STIM1). SOCE was observed in VSMCs that were without either S1P2 or S1P3 receptors, and intracellular S1P activated SOCE by STIM1 recruitment to the plasma membrane, strongly suggesting that not only extracellular but also intracellular S1P can activate SOCE. Furthermore, they showed that the S1Pinduced SOCE contributes to constriction of cerebral arteries. The role of intracellular S1P on SOCE will be further discussed in Section 5, which addresses the role of sphingosine kinase in VSMCs. Transient receptor potential canonical (TRPC) proteins are now believed to have an important role in not only SOCE but also receptoroperated Ca2þ entry (ROCE). In fact, S1P reportedly activates TRPC5 in human saphenous vein SMCs (22). TRPC5 is expressed in the SMCs of human veins together with TRPC1, which forms a complex with TRPC5, and S1P also activates TRPC5-TRPC1 heteromultimeric channels. Furthermore, we have found that S1P can cause not only SOCE but also ROCE in VSMCs (24), but the mechanisms of ROCE by S1P are still largely unknown. Further studies are required to clarify the detailed mechanisms. There is increasing evidence that the immune modulator FTY720, which is used as a treatment for multiple sclerosis, might also be applied to cardiovascular diseases such as atherosclerosis. FTY720 is phosphorylated by sphingosine kinase, and the phosphorylated compound is a potent agonist of S1P receptors, except S1P2. In fact, FTY720 phosphate (FTY720-P) induces an increase in [Ca2þ]i in Chinese hamster ovary (CHO) cells that stably express the S1P3 receptor (25). Moreover, various selective S1P receptor agonists have become commercially available. In addition to FTY720-P, they could be useful tools to elucidate further the physiological roles of S1P receptors in vascular cells. 3. Eicosanoid production Eicosanoids produced by cyclooxygenase (COX) in the vascular wall have important roles in cardiovascular pathophysiology. There are two isoforms of COX: COX-1 and COX-2. COX-1 is constitutively expressed in most cells, whereas COX-2 is induced in certain cell types including VSMCs. Recent studies have implicated a regulatory function of sphingolipids in prostanoid production (29). S1P reportedly induces COX-2 expression and subsequently produces prostanoids in many cells such as aortic SMCs (12, 18, 30), coronary artery SMCs (17), tracheal SMCs (31), renal mesangial cells (32), and human amnionderived WISH cells (33). In aortic SMCs, we reported that S1P (>1 mM) significantly induced prostaglandin I2 (PGI2) production (Fig. 2A), which is major arachidonic metabolite in rat aortic SMCs (18). S1P-induced COX-2, but not COX-1, expression in VSMCs. Both S1P2 and S1P3 receptors seem to mediate the induction of COX-2 by S1P. Previously, we showed that suramin, an S1P3 receptor antagonist, significantly inhibited S1P-induced COX-2 expression (Fig. 2B). In addition, we confirmed that the selective S1P2 receptor antagonist JTE-013 (10 mM) also significantly inhibited COX-2 expression (unpublished data). JTE-013 has been reported to inhibit the specific binding of radiolabeled S1P to membranes of CHO cells transfected with human and rat S1P2 receptors, with IC50 values of 17 ± 6 and 22 ± 9 nM, and has been reported to not affect S1P binding to S1P3 and S1P1 at concentrations up to 10 mM (34e36). In agreement with our results, both S1P2 and S1P3 receptors have been shown to be necessary for COX-2 induction in human aortic SMCs (12). In coronary artery SMCs, Damirin et al. (17) suggested that S1P-induced cAMP accumulation caused by PGI2 synthesis is mediated mainly by the S1P2 receptor, although they have not directly elucidated which S1P receptor subtype is responsible for COX-2 induction. It has been reported that S1P
3
activates nucleocytoplasmic shuttling of the mRNA-stabilizing protein HuR, which in turn stabilizes COX-2 mRNA and elicits COX-2 expression in macrophages (37). Thus, S1P presumably increases COX-2 expression by inducing transcription of COX-2 mRNA and by stabilization of its mRNA in VSMCs. Increased [Ca2þ]i by S1P has an important role in COX-2 induction, since S1P has no effect on COX-2 expression under extracellular and intracellular Ca2þ-depleted conditions and a protein kinase C (PKC) inhibitor inhibits COX-2 induction (18). This Ca2þdependent activation of PKC might be mediated by Gi and Gq, but not G12/13, protein-coupled S1P receptors. Inhibition of Gi protein by PTX partially inhibited COX-2 induction, while inhibition of Rho kinase, which is the main signaling molecule of G12/13 protein, failed to inhibit COX-2 induction. Growing evidence suggests that HDL-associated S1P has a role in the vascular protective effects of HDLs. In addition to their role in reverse cholesterol transport, HDLs also exert beneficial effects on anti-oxidative, anti-inflammatory, anti-thrombotic, and endothelium-dependent vasorelaxation (38,39). S1P is known as the most active lipid component of HDLs and plays a key role in vascular biology as an extracellular mediator (10). HDLs increase PGI2 synthesis in both VSMCs and endothelial cells through a mechanism involving COX-2 induction (12). Furthermore, both HDL- and S1P-induced COX-2 inductions are diminished by either S1P receptor antagonists (suramin, JTE-013, or VPC 23019) or transfection of S1P2 and S1P3 siRNA (12). COX-2-derived prostanoids are now believed to be key protective molecules for the cardiovascular system (40). Enhanced COX-2 induction in vascular walls is considered to function primarily as a defensive and compensatory mechanism for the lack of endothelial COX-1 function at the site of a local vascular injury associated with thrombosis, atherosclerosis, and hypertension. In addition to its vasodilating action, PGI2 has inhibitory effects on platelet aggregation and adhesion, leukocyte adhesion, and VSMC proliferation/migration (41). In fact, we reported that the production of PGI2 and interleukin-1b (IL-1b)-induced COX-2 protein expression were lower in VSMCs from spontaneously hypertensive rats-stroke prone (SHRSP) than from normotensive Wistar Kyoto rats (42). It is worthy to note that S1P-induced COX-2 expression in airway SMCs is also considered to have a protective effect against asthma, because of the enhancement of PGE2 production, which represses b2-adrenergic activity by receptor desensitization (43). As we discussed above, [Ca2þ]i elevation by S1P starts at a concentration of more than 0.001 mM, and a significant increase in both peak and sustained [Ca2þ]i was observed at more than 0.1 mM, while PGI2 release by S1P starts at a concentration of more than 0.1 mM. The nano-molar order of the S1P-induced increase in [Ca2þ]i may have a physiological role in VSMCs, but the excessive elevation of [Ca2þ]i by a micro-order of S1P may cause abnormal vasoconstriction. The PGI2 released by S1P may have a role in the amelioration of the abnormal situation via autocrine and/or paracrine action.
4. Nitric oxide production Nitric oxide (NO) produced by NO synthase (NOS) in the vascular wall plays important roles in cardiovascular pathophysiology. In addition to its vasodilating action, NO has inhibitory effects on platelet aggregation and adhesion, leukocyte adhesion, and VSMC proliferation/migration (44). There are three isoforms of NOS: neuronal NOS, inducible NOS (iNOS), and endothelial NOS (eNOS). eNOS is restricted to the endothelium, while iNOS is expressed in several cell types including VSMCs following stimulation with cytokines such as IL-1b.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
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T. Machida et al. / Journal of Pharmacological Sciences xxx (2016) 1e7
B
A
COX-2 Relative expression (%)
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Fig. 2. S1P induces PGI2 production and COX-2 expression in cultured rat VSMCs. A: PGI2 production was determined by radioimmunoassay. The cells were treated with various concentrations of S1P for 24 h. B: S1P induces COX-2 expression via S1P3 receptor. COX-2 protein expression was determined by western blotting. The cells were pretreated with or without suramin (100 mM) for 1 h and then treated with or without S1P (1 mM) for 4 h. Upper: A representative image. Lower: Densitometric analysis expressed taking samples treated with S1P alone as 100%. Bars show mean ± S.E.M. values of 4 and 6 experiments for A and B, respectively. **P < 0.01, vs. control. ##P < 0.01 vs. S1P alone. Adopted from Ref. (18) with permission.
We reported that S1P (>0.1 mM) inhibited IL-1b-induced NO production and iNOS expression in VSMCs (19) (Fig. 3). This iNOS inhibition was inhibited partially by PTX (19) (Fig. 3). Since this effect of PTX disappeared under the Ca2þ-depleted condition, S1P-induced iNOS inhibition was mediated partially by Ca2þdependent Gi protein coupled to the S1P receptor. Conversely, the Rho kinase inhibitor Y 27632 partially but significantly attenuated the inhibitory effect of S1P on iNOS expression in the Ca2þdepleted condition, but did not affect it in the presence of Ca2þ. S1P also significantly inhibited the IL-1b-induced persistent activation of extracellular signal-regulated kinase (ERK), which is necessary for IL-1b-induced iNOS expression, but had no effect in the Ca2þ-depleted condition. This ERK inhibition was probably mediated by Gq protein, because PTX did not affect this ERK inhibition. Taken together, we conclude that S1P inhibits IL-1binduced iNOS expression in rat VSMCs through multiple mechanisms involving both PTX-sensitive and -insensitive G proteins coupled to S1P receptors. Furthermore, Ca2þ-dependent ERK inhibition and Ca2þ-independent Rho kinase activation are involved in the inhibitory mechanism of iNOS inhibition. We have also observed that JTE-013 (10 mM) impaired the inhibitory effect of S1P on iNOS protein expression, suggesting that the S1P2 receptor at least has a role in S1P-induced iNOS inhibition (unpublished data). In agreement with our results, S1P inhibits
IL-1b-induced iNOS expression in rat mesangial cells and bovine/ human chondrocytes (45e47). Although signal transduction seems to be different between these cells, this iNOS inhibition is mediated by S1P2 receptor activation, since both JTE-013 and knockdown of the S1P2 receptor by transfection with S1P2 siRNA fully reversed IL-1b-induced iNOS expression in human chondrocytes (47). Counteraction of IL-1b-induced iNOS expression by S1P in chondrocytes from osteoarthritis patients may help to prevent chronic inflammation. However, since iNOS induction in VSMCs is also considered to function primarily as a defensive and compensatory mechanism for the lack of endothelial function at the site of a local vascular injury associated with thrombosis, atherosclerosis, and hypertension, S1P inhibition of NO production in VSMCs may be of relevance to local pathophysiological conditions. In fact, iNOS expression in VSMCs is negatively modulated by a variety of vasoactive mediators such as angiotensin II (48) and 5-hydroxytryptamine (49,50), which cause vessel contraction and VSMC proliferation. Furthermore, we reported that IL-1b-induced NO production and iNOS expression in VSMCs derived from SHRSP and under pressure stress, which simulates systolic hypertension, were lower than in control cells (19,42). Therefore, selective S1P2 receptor antagonists may be helpful therapeutically, in view of their antagonism of iNOS inhibition by S1P.
B Relative NO production (%)
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Fig. 3. S1P inhibits IL-1b-induced NO production and iNOS expression in cultured rat VSMCs. The cells were untreated or pretreated with PTX (400 mg/ml) for 24 h. Cells were then stimulated with IL-1b for 24 h in the absence or presence of various concentrations of S1P. A: NO production in the culture medium was measured by NOx Autoanalyzer (ENO-10, Eicom, Kyoto, Japan). Amount of NO expressed as a percentage, taking samples treated with IL-1b alone as 100%. Bars show mean ± S.E.M. values of 4 experiments. **P < 0.01 vs. IL1b alone. B: A representative image of iNOS protein expression. The protein expression was determined by western blotting. b-Actin protein expression was also evaluated as a loading control. Adopted from Ref. (19) with permission.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
T. Machida et al. / Journal of Pharmacological Sciences xxx (2016) 1e7
NO signaling pathways (52). Although S1P negatively regulates iNOS expression in VSMCs as mentioned above, it is possible that the intracellular S1P generated by SphK1 affects iNOS expression via autocrine/paracrine signaling mechanisms in VSMCs. In fact, our preliminary experiments showed that DMS significantly potentiated IL-1b-induced iNOS expression and NO production in VSMCs (unpublished data).
5. Role of sphingosine kinase in VSMCs Recently, VSMCs have been shown to generate S1P intracellularly by sphingosine kinase (SphK) from sphingosine. Two isoforms of SphK have been identified: SphK1 and SphK2. Zhu et al. (51) reported that corticotrophin-releasing factor (CRF) accelerates S1P synthesis by inducing SphK1 expression in both A7r5 cells and rat primary VSMCs. They showed that the synthesized S1P is secreted and activates the S1P3 receptor. Since the SphK inhibitor dimethylsphingosine (DMS) and the S1P3 receptor antagonist CAY 10444 inhibit CRF-induced VSMCs migration, they concluded that S1P generation and S1P3 activation in VSMCs are responsible for CRF-induced migration. Wilson et al. (28) have reported that intracellular S1P generated by SphK1 has an important role in angiotensin II (Ang II)-induced SOCE in VSMCs, showing that Ang II activates SphK activity and increases intracellular S1P. They also found that Ang II induces biphasic Ca2þ entry, consisting of an immediate peak due to inositol tris-phosphate-dependent release of intracellular Ca2þ, followed by a sustained transmembrane Ca2þ influx through SOCE, and that inhibition of SphK1 attenuates the second phase of Ca2þ influx. Furthermore, they found that genetic deletion of SphK1 significantly inhibits both the acute hypertensive response to Ang II in anaesthetized SphK1 knockout mice and the sustained hypertensive response to continuous infusion of Ang II in conscious animals. This indicates that SphK1 in VSMCs plays a critical role in the development of Ang II-induced hypertension. In mouse BV2 microglial cells activated with lipopolysaccharide, DMS inhibits iNOS mRNA expression, suggesting that SphK1 regulates
A Endothelial dysfunction
5
6. Clinical relevance Under normal physiological conditions, vasoactive agents derived from the endothelium and other tissues modulate endothelial cell and VSMC function to maintain vascular homeostasis, including vascular tone. Kerage et al. (53) have reported that physiologically low concentrations of S1P (ca. 0.1 mM) are thought to maintain the endothelial barrier, while pathophysiological concentrations of S1P (ca. 10 mM) disrupt the endothelial barrier and increase vascular permeability. This indicates that S1P itself at high concentrations, as well as other circulating vasoconstrictors, reaches VSMCs through endothelial leakage. The high concentration of S1P can cause an increase in [Ca2þ]i and induce PGI2 production in VSMCs via the S1P3 receptor as we mentioned above. S1P is known to play important roles in the pathogenesis of atherosclerosis. Although the S1P3 receptor has been reported to have some atheroprotective effects (12,54), the S1P2 receptor instead plays a critical role in the development of atherosclerosis. Twenty weeks of FTY720 treatment in apolipoprotein E deficient mice that were fed a high-cholesterol diet dramatically reduced
Disrupted endothelial barrier
S1P
eNOS, COX-1
eNOS, COX-1
S1P VSMCs
S1P2
S1P3
COX-2 expression PGI2 production
COX-2 expression PGI2 production
iNOS expression NO production
[Ca2+]i
B
S1P concentration Low (<0.1 μM)
High (>1 μM)
[Ca2+]i PGI2 production
Ameliorate the abnormal VSMCs function ?
NO production Fig. 4. Possible mechanisms of modulating VSMCs functions by S1P at a local site of vascular injury, such as atherosclerotic lesion. A: Role of S1P2 and S1P3 receptors in VSMCs. B: The concentration-dependent changes of VSMCs function by S1P.
Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010
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atherosclerotic lesion volume, macrophage, and collagen content (55). Inhibition of the release of monocyte chemoattractant protein-1 (MCP-1) via S1P3 receptor by VSMCs is thought to be involved in the mechanisms. Wang et al. (56) have reported that S1P2 receptor was expressed in macrophages, endothelial cells, and SMCs in atherosclerotic aortas. In S1pr2/Apoe/ mice fed a highcholesterol diet, the area of atherosclerotic plaques was markedly decreased compared with S1pr2þ/þApoe/ mice. S1P2 receptor in monocytes/macrophages promotes atherosclerosis through mechanisms including the regulation of modified LDL accumulation, cytokine production, and cell migration. The activation of S1P2 receptors in endothelial cells inhibits eNOS activation and promotes proinflammatory cytokines such as MCP-1. In VSMCs, the activation of S1P2 receptor is assumed to destabilize plaques by decreasing the density of a-smooth muscle actin-positive SMCs, which is likely mediated through the inhibition of proliferation and SMC migration into the intima. As we mentioned above, S1P is known as the most active lipid component of HDL, an atheroprotective lipoprotein. Some atheroprotective effects of HDL such as eNOS activation were shown to be mediated via the S1P3 receptor (54). Thus, at local pathophysiological sites with endothelial dysfunction, iNOS inhibition by S1P2 receptor activation in VSMCs may further magnify the atherosclerosis. In this way, selective S1P2 receptor antagonists may be helpful therapeutically for cardiovascular diseases, by antagonizing of iNOS inhibition by S1P. 7. Conclusion As shown in Fig. 4A, at a local site of vascular injury, some vasoactive mediators such as prostaglandins and NO produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. A large amount of S1P is released from activated platelets into the plasma, and this S1P is considered to affect the functions of VSMCs directly and dramatically. More than 1 mM S1P significantly induces an increase in [Ca2þ]i via S1P3 receptor activation, while it significantly decreases IL-1b-induced NO production via S1P2 receptor activation. COX-2 induction by S1P stimulation is mediated by both S1P2 and S1P3 receptor activation (Fig. 4A). As discussed above, the excessive elevation of [Ca2þ]i and the inhibition of NO production by a micro-order of S1P may cause abnormal vasoconstriction. The PGI2 released by S1P may have a role in the amelioration of the abnormal situation via autocrine and/or paracrine action (Fig. 4B). Furthermore, selective S1P2 receptor antagonists may be helpful therapeutically for cardiovascular diseases, in view of their antagonism of iNOS inhibition by S1P. Further progress in studies for the precise cellular and molecular mechanisms of S1P may provide useful knowledge for the development of new S1P-related drugs for the treatment of cardiovascular diseases. Conflict of interest The authors declare no conflict of interest. References (1) Yatomi Y, Ozaki Y, Ohmori T, Igarashi Y. Sphingosine 1-phosphate: synthesis and release. Prostaglandins Other Lipid Mediat. 2001;64:107e122. (2) Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316:295e298. (3) Hla T, Venkataraman K, Michaud J. The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta. 2008;1781:477e482.
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Please cite this article in press as: Machida T, et al., Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate, Journal of Pharmacological Sciences (2016), http://dx.doi.org/10.1016/j.jphs.2016.05.010