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• W2003128599 abstract "EDITORIAL FOCUSExtracellular ATP: a central player in the regulation of vascular smooth muscle phenotype. Focus on “Dual role of PKA in phenotype modulation of vascular smooth muscle cells by extracellular ATP”David ErlingeDavid ErlingePublished Online:01 Aug 2004https://doi.org/10.1152/ajpcell.00217.2004MoreSectionsPDF (75 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat the extracellular nucleotides ATP, ADP, UTP, and UDP are potent growth factors for vascular smooth muscle cells (VSMC) by actions on P2Y receptors (7, 9, 14, 20). The growth-stimulating effects may be of importance in the development of atherosclerosis, neointima after balloon angioplasty, chronic vascular rejection after transplantation, and hypertension (3). In these processes a central mechanism is the change of the VSMC from a highly differentiated contractile phenotype into a proliferative, more fibroblast-like synthetic phenotype (18). Extracellular nucleotides have different effects depending on phenotype. In the contractile phenotype, ATP acts as an important stimulator of VSMC contraction. For example, knockout experiments have shown that the ATP receptor P2X1 contributes to 50% of the sympathetic vasoconstriction in mice (19). By contrast, in the synthetic phenotype, extracellular nucleotides contribute to the mitogenic response.In the current article in focus (Ref. 8, see p. in this issue), Hogarth et al. show that ATP has a dual concentration-dependent effect on the VSMC phenotype. Low ATP concentrations stimulate expression of genes specific for the contractile phenotype. High ATP concentrations cause a phenotypic shift from the contractile to the synthetic phenotype, and this shift is dependent on a transient activation of protein kinase A (PKA), which inhibits activation of a serum response factor (SRF). This previously unrecognized mechanism also appears to be responsible for the profound mitogenic effect of ATP.Mitogenic EffectsIn contrast to the previously documented inhibitory effect of the intracellular second messenger cAMP on VSMC mitogenesis (13), Hogarth et al. (8) report that ATP-mediated activation of PKA is necessary for a maximum stimulation of DNA synthesis. If the adenylyl cyclase activator forskolin and the β-adrenergic agonist isoproterenol were used to induce a prolonged PKA stimulation, mitogenesis was inhibited. By contrast, transient PKA stimulation evoked by ATP not only stimulated mitogenesis but also appeared to be necessary for the maximum mitogenic effect. However, when the authors tried to mimic the transient PKA stimulation by brief stimulation with forskolin, this treatment resulted in loss of the inhibitory effect but did not stimulate DNA synthesis. Thus the positive role of PKA in ATP-induced DNA synthesis cannot be explained solely by the transient duration of PKA activity induced by the agonist. Hogarth et al. suggest that an ATP stimulation of the PKA substrate vasodilator-stimulated phosphoprotein (VASP) could be crucial, but further studies are needed to confirm this possibility.Hogarth et al. (8) also found that ERK1/2 was stimulated at both low and high concentrations of ATP. Interestingly, ERK1/2 activation was not inhibited by a high-efficiency adenovirus-mediated expression of the PKA inhibitor protein kinase I (PKI), even though DNA synthesis in response to high ATP was inhibited. Thus ATP stimulation of ERK1/2 is not dependent on PKA activation. In contrast, both ERK1/2 and transient PKA stimulation were found to be crucial for the major DNA stimulation by high-dose ATP, but on its own, ERK1/2 phosphorylation was not sufficient. On the other hand, low-dose ATP stimulation of DNA synthesis was shown to be ERK1/2 dependent but PKA independent. Thus ERK1/2 is required, but not sufficient, for profound DNA synthesis.VSMC PhenotypeThe phenotypic shift is a central mechanism for smooth muscle cell participation in the development of vascular disease. The cells lose contractile proteins, start to produce growth factors and matrix, become less differentiated and more fibroblast-like, begin to migrate, and proliferate (18). In the article in focus, Hogarth et al. report that low concentrations of ATP stimulated the activity of SRF. SRF is implicated in the transcription of VSMC-specific genes. Low concentrations of ATP also stimulated expression of SM22 and SM-α-actin, which are proteins specific for the contractile phenotype. By using an adenovirus encoding a DNA binding-deficient SRF mutant with dominant negative properties, the authors confirm that stimulation of SM22 and SM-α-actin expression by low ATP concentration is mediated by SRF activation. High concentrations of ATP, on the other hand, inhibited both SRF activity and the expression of VSMC-specific proteins, indicating a conversion into a synthetic phenotype. This was dependent on the transient PKA activation described above.Interestingly, the change from the contractile to the synthetic phenotype is also characterized by downregulation of the contractile P2X1 receptor and upregulation of mitogenic P2Y receptors (6, 17). The P2X1 receptor is specific for the contractile VSMC (1, 21). Among P2 receptors, that subtype has the highest expression in VSMC in the intact vessel wall, and its expression is lost during cell culture (6). Shear stress, which is known to release ATP (2), induces changes in VSMC that are similar to a shift toward a more synthetic phenotype (22). Furthermore, high concentrations of ATP upregulate the expression of the mitogenic P2Y receptors P2Y2 and P2Y6 (9, 11). Hogarth et al. (8) provide a possible mechanism for the observed ATP-induced upregulation of P2Y receptors via transient stimulation of cAMP and PKA with a subsequent decrease in SRF activity. This could explain the observed forskolin-induced upregulation of P2Y2 receptors (10). It will be of interest to test for direct evidence for the link between SRF and P2 receptor regulation.P2 Receptor PharmacologyNucleotide receptor pharmacology is complex because of the large number of P2 receptor subtypes and the limited availability of selective antagonists (16). Hogarth et al. (8) thus used various agonists to help define the role of specific P2Y receptor subtypes in the responses they studied. They were able to show that ADP receptors do not mediate the transient PKA activation, thereby excluding P2Y1, P2Y12, and P2Y13 receptors. Because UTP stimulation of DNA synthesis was PKA dependent only to a small extent, this finding excluded P2Y2 and P2Y4 receptors. Such results are in agreement with results in previous studies in other cell types in which different cAMP activation pathways for ATP and UTP were described (15). Use of adenosine 5′-O-(3-thiotriphosphate) (ATPγS), which is resistant to degradation, and lack of inhibitory effect of an adenosine antagonist excludes participation of adenosine receptors and also the recently cloned adenosine and AMP receptor P2Y15, which reportedly stimulates both inositol 1,4,5-trisphosphate (IP3) and cAMP (12). Thus, by exclusion of other possible ATP receptors, the evidence suggests involvement of the P2Y11 receptor (4). This receptor also stimulates both IP3 and cAMP, but the physiological role of this activation of multiple second messengers has not been clarified. In the VSMC, IP3 and cAMP usually have opposite roles: contraction vs. relaxation or growth stimulation vs. inhibition. The present study offers a possible physiological role in which specific activation of these second messengers may be synergistic and necessary for ATP stimulation of DNA stimulation and phenotype change.Actions of the P2Y11 receptor have not been shown previously in VSMC. However, on the basis of mRNA quantification in human VSMC, P2Y11 and P2Y6 receptors are the next most highly expressed P2Y receptor subtypes after P2Y2 (21). Further studies are necessary to firmly establish that the effects described by Hogarth et al. (8) are mediated by P2Y11 receptors.The current results link previous results together in a model for ATP regulation of the VSMC (Fig. 1). Low or high ATP concentrations may determine VSMC phenotype and proliferation. In a situation with intact endothelium, the VSMC is protected against high ATP concentrations by endothelial ectonucleotidases; the low concentrations of ATP maintain VSMC in a contractile phenotype. This is important because in this situation VSMC regulate tone by contracting in response to ATP released from sympathetic nerves (19). Endothelial denudation results in VSMC proliferation (Fig. 1B). This has previously been explained by other mechanisms, for example, loss of endothelial NO (5). The work of Hogarth et al. suggests a new mechanism, namely, that the loss of endothelial ectonucleotidases results in exposure of the VSMC to high ATP levels, stimulating both growth and a shift into a synthetic phenotype. The synthetic phenotype is both proliferative and causes increased matrix deposition, resulting in stenosis of the vessel. The present study by Hogarth et al. provides data suggesting that ATP-stimulated transient PKA activation mediating inhibition of SRF may have a central role in both these processes.Fig. 1.Low or high ATP concentrations may determine vascular smooth muscle cell (VSMC) phenotype. A: in a situation with intact endothelium, the VSMC is protected against high ATP levels by endothelial ectonucleotidases, and the low ATP levels keep the VSMC in a contractile phenotype by stimulating serum response factor (SRF) activity. In this situation the VSMC regulates tone by contracting in response to ATP released from sympathetic nerves. SNS, sympathetic nerve stimulation. B: endothelial denudation results in loss of endothelial ectonucleotidases and exposure of the VSMC to high ATP levels from platelets, inflammatory cells, and red blood cells, stimulating growth and a shift into a synthetic phenotype. The synthetic phenotype is proliferative, causing increased matrix deposition, decreased expression of contractile P2X1, and increased expression of mitogenic P2Y receptors. ATP-stimulated transient protein kinase A (PKA) activation mediating inhibition of SRF may have a central role in these processes.Download figureDownload PowerPointREFERENCES1 Bo X, Sexton A, Xiang Z, Nori SL, and Burnstock G. Pharmacological and histochemical evidence for P2X receptors in human umbilical vessels. Eur J Pharmacol 353: 59–65, 1998.Crossref | PubMed | ISI | Google Scholar2 Bodin P, Bailey D, and Burnstock G. Increased flow-induced ATP release from isolated vascular endothelial cells but not smooth muscle cells. Br J Pharmacol 103: 1203–1205, 1991.Crossref | PubMed | ISI | Google Scholar3 Burnstock G. Purinergic signaling and vascular cell proliferation and death. 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Erlinge, Dept. of Cardiology, Lund Univ., SE-221 85 Lund, Sweden (E-mail: [email protected]). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByCellular and molecular effects of hyperglycemia on ion channels in vascular smooth muscle27 June 2020 | Cellular and Molecular Life Sciences, Vol. 78, No. 1Extracellular ATP induces fast and transient non-selective cationic currents and cytosolic Ca2+ changes in human umbilical artery smooth muscle cells4 October 2011 | Purinergic Signalling, Vol. 8, No. 2P2Y receptors as regulators of lung endothelial barrier integrityJournal of Cardiovascular Disease Research, Vol. 2, No. 1Inhibition of neutrophil-mediated production of reactive oxygen species (ROS) by endothelial cells is not impaired in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis patients7 May 2010 | Clinical and Experimental Immunology, Vol. 161, No. 2Extracellular Purines in Endothelial Cell Barrier Regulation1 March 2010Attenuated Purinergic Receptor Function in Patients With Type 2 Diabetes6 October 2009 | Diabetes, Vol. 59, No. 1α1D-Adrenergic receptor insensitivity is associated with alterations in its expression and distribution in cultured vascular myocytes4 December 2009 | Acta Pharmacologica Sinica, Vol. 30, No. 12Functional coupling expression of COX-2 and cPLA2 induced by ATP in rat vascular smooth muscle cells: role of ERK1/2, p38 MAPK, and NF-κB20 February 2009 | Cardiovascular Research, Vol. 82, No. 3ATP Release from Vascular Endothelia Occurs Across Cx43 Hemichannels and Is Attenuated during Hypoxia30 July 2008 | PLoS ONE, Vol. 3, No. 7Binding of the P2Y 2 Nucleotide Receptor to Filamin A Regulates Migration of Vascular Smooth Muscle CellsCirculation Research, Vol. 102, No. 5High Glucose Activates Nuclear Factor of Activated T Cells in Native Vascular Smooth MuscleArteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26, No. 4The P2X 7 Receptor Sustains the Growth of Human Neuroblastoma Cells through a Substance P–Dependent Mechanism19 January 2006 | Cancer Research, Vol. 66, No. 2The Effects of Extracellular Purines and Pyrimidines on Human Airway Smooth Muscle Cells12 August 2005 | Journal of Pharmacology and Experimental Therapeutics, Vol. 315, No. 2 More from this issue > Volume 287Issue 2August 2004Pages C260-C262 Copyright & PermissionsCopyright © 2004 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00217.2004PubMed15238358History Published online 1 August 2004 Published in print 1 August 2004 Metrics" @default.
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