© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Signalling mechanisms underlying the myogenic response in human subcutaneous resistance arteries
aSchool of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Road, Glasgow, Scotland, UK
bDepartment of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, UK
* Corresponding author. Tel.: +44-141-331-3209; fax: +44-141-331-3208 p.coats{at}gcal.ac.uk
Received 28 June 2000; accepted 29 November 2000
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: In this study we have examined for the first time the signal transduction mechanisms involved in the generation of pressure-dependent myogenic tone in human small resistance arteries from the subcutaneous vascular bed. Methods: Myogenic responses and the subcellular mechanisms involved in the generation of this response were studied on a pressure myograph. Results and conclusion: Human subcutaneous resistance arteries constricted 14.1±1.1% in response to an increases in intraluminal pressure from 40 to 80 mmHg and a further 3.5±1.7% in response to the 80–120-mmHg pressure step. Ca2+ depletion or nifedipine abolished this response, whereas BAY K 8644 increased this response to 20.6±2.1% (P<0.05, response vs. control). The phospholipase C inhibitor U-73122 reduced the myogenic response to 2.5±1.0% at 80 mmHg (P<0.01, response vs. control) and abolished it at 120 mmHg. Diacylglycerol lipase inhibition with RHC-80267 abolished all myogenic responses to pressure. The protein kinase C (PKC) activator phorbol 12,13-dibutyerate increased the maximal myogenic response to 20.9±1.8% (P<0.05, response vs. control), whereas the PKC inhibitor calphostin C abolished myogenic responses. These data show that the generation of pressure-dependent myogenic tone in human subcutaneous arteries is dependent on Ca2+ influx via voltage operated Ca2+ channels (VOCCs) and a concomitant requirement for the activation of phospholipase C (PLC), diacylglycerol, and PKC.
KEYWORDS Signal transduction; Microcirculation; Contractile function; Protein kinases; Ca-channel; Calcium (cellular)
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The myogenic response refers to the intrinsic property of blood vessels to respond dynamically to changes in intraluminal pressure in a manner independent of neurohormonal modulation [1]. The degree of myogenic tone in blood vessels is positively correlated with blood pressure, i.e. an increase in intraluminal pressure results in an increase in myogenic tone (constriction) and conversely a decrease in intraluminal pressure results in a decrease in myogenic tone (relaxation). Although first described by Bayliss in 1902 [2], to date the mechanisms underlying this response have not been fully determined. Myogenic mechanisms of vascular tone have been studied extensively in numerous animal models and are presently considered to be a major determinant of peripheral vascular resistance and regulation of regional blood flow in response to changes in blood pressure [1,3,4]. Unsurprisingly, myogenic tone is most important in the small resistance arteries <200 µm [5].
The signal transduction mechanisms involved in the generation of myogenic tone are complex [1]. Following a number of animal studies, it is currently postulated that myogenic responses are initiated as a consequence of pressure-dependent modification of vascular smooth muscle wall tension and subsequent activation of mechanosensitive ion channels [6–12]. This in turn results in membrane depolarisation and an influx of Ca2+ via voltage operated Ca2+ channels (VOCCs) [13–15]. The Ca2+ influx is accompanied by activation of membrane bound enzymes and second messenger protein kinases that result in an increase in contractile myofilament sensitivity to Ca2+ [16–19]. The net result of the Ca2+ influx and enhancement of myofilament sensitivity to Ca2+ is activation of the contractile apparatus and subsequently an increase in vascular tone.
Knowledge of myogenic mechanisms of vascular tone is based on animal models and therefore the mechanisms involved in the generation of pressure-dependent myogenic tone in human resistance arteries are not well established. In this study we have for the first time investigated the myogenic phenomenon in human subcutaneous resistance arteries.
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2 Methods |
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2.1 Patients and vessel preparation
The investigation conforms with the principles outlined in the Declaration of Helsinki [20]. Healthy volunteers with no history of vascular disease, diabetes, hypertension or renal impairment attended the Clinical Investigations Research Unit at the Western Infirmary, Glasgow. Clinical characteristics of the patients are given in Table 1. Prior to the excision of a subcutaneous gluteal fat biopsy (1.5x1.5x0.5 cm), excised under local anaesthesia with 1% lidocaine, each subject gave informed written consent. Biopsies were immediately transferred to the laboratory in cold physiological saline solution (PSS). A total of 34 subcutaneous resistance-size arteries (lumen diameter 114±6 µm) were isolated from 25 biopsies and cleaned of any adherent tissue under a dissection microscope (Zeiss Stemi 2000, magnification x6 to x45).
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Isolated arteries were studied on a pressure myograph (Danish MyoTech P100). The myograph block containing the double cannulated and pressurised arteries was placed on the stage of a Zeiss Axiovert 25C inverted microscope. A real time image of the artery (752x582 pixels) was obtained by a high-resolution 16-bit CCD Sony XC-73CE monochrome video camera attached to the microscope's third ocular tube. A digital DT3157 Mach frame grabber (Data Translation, Guildford, UK) processed the digital image. The final viewed magnification of the prepared artery was x100. The video image was analysed using Vessel View software (Danish MyoTech, Aarhus, Denmark). Vessel View permitted the measurement of multiple parameters; edge detection of the viewed image provided measurement of external diameter, internal diameter, wall thickness and lumen diameter. Additionally, time, pressure, temperature and manual intervention were recorded. Data were acquired at time intervals of 1 s and recorded on a personal computer.
On isolation, all arteries were transferred to the 10-ml pressure myograph organ bath where they were immersed in PSS. On transfer, one end of the artery was cannulated and secured with two fine nylon sutures to a hollow glass micro-cannula (outside diameter 75 µm). The lumen was flushed gently with PSS to remove any blood or debris, following which the second end of the artery was cannulated and secured to a second micro-cannula (outside diameter 75 µm) and the artery pressurised to 10 mmHg. The PSS was gradually warmed to 37°C over a period of 15 min. Arteries were gradually pressurised from 10 to 40 mmHg over a period of 
15 min. All preparations were gassed with 95% O2/5% CO2 maintaining pH 7.4. Following mounting and pressurisation, all preparations were given a period of 1-h equilibration at an intraluminal pressure of 40 mmHg in a no flow state. Functional viability was assessed by maximal vasoconstriction to 60 mm K+ PSS and noradrenaline (10 µM) and vasorelaxation (<80%) to acetylcholine (10 µM). All arteries fulfilled these criteria and none were discarded.
2.2 Assessment of myogenic response and myogenic tone
Arterial myogenic responses were studied by increasing the intraluminal pressure from 40 to 120 mmHg in 40-mmHg steps for a period of 15 min at each pressure step. Vessel diameter measurements were taken immediately prior to the subsequent pressure step. Finally, the intraluminal pressure was readjusted to 40 mmHg. Preliminary studies in our laboratory had shown that 40 mmHg is below the threshold for myogenic activation in these arteries. To determine total myogenic tone the PSS was then replaced with Ca2+ free PSS containing 1 mm ethylene glycol-tetra acetic acid (EGTA). Following an incubation period of 30 min in the Ca2+ free PSS sarcoplasmic reticulum stores were exhausted by a single transient exposure (2 min) to 20 mm caffeine. Addition of caffeine produced a transient vasoconstriction that was not reproducible upon subsequent applications. Finally, with no free Ca2+ available to the artery, the pressure step 40–80–120 mmHg was repeated. The difference in lumen diameter (LD) of the artery before and after Ca2+ depletion was considered as a measure of total myogenic tone [21]:
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Myogenic vasoconstriction responses (reduction in diameter relative to pressure step) were calculated as follows:
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ID is the change in internal diameter and IDorig is the internal diameter at the previous intraluminal pressure.
2.3 Identification of myogenic mechanisms
To ascertain a role for VOCCs in the generation of myogenic tone, following a control response pressure curve (40–80–120 mmHg) the curve was repeated following a 30-min incubation period with the VOCC inhibitor nifedipine (1 and 10 µm) or in the presence of the VOCC activator BAY K 8644 (10 and 100 nm). To determine an involvement of sarcoplasmic reticulum (SR) in development of pressure-dependent myogenic tone responses were measured before and after a 30-min incubation period with the SR ryanodine receptor inhibitor ryanodine (10 µm) or the SR Ca2+-ATPase pump inhibitor cyclopiazonic acid (CPA, 10 µm). A role for phospholipase C (PLC) in the myogenic response was determined by repeating pressure curves following a 15-min incubation period with the PLC inhibitor U-73122 (2 µm). The contribution of diacylglycerol to the myogenic response was investigated using the membrane permeable analogue of diacylglycerol, 1-oleoyl-2-acetyl sn-glycerol (OAG) and the diacylglycerol lipase inhibitor RHC-80267. Pressure-dependent responses were measured before and after a 30-min incubation period with OAG or RHC-80267. The involvement of protein kinase C (PKC) in the myogenic response was investigated using the PKC activator phorbol 12,13-dibutyerate (PDBu, 10 and 30 nm) and the PKC inhibitor calphostin C (30 and 100 nm). Pressure-dependent responses were repeated in the presence of PDBu or following a 30-min incubation period with calphostin C.
2.4 Drugs and solutions
Acetylcholine, nifedipine, norepinephrine, PDBu and ryanodine were purchased from Sigma (Poole, Dorset, UK). BAY K 8644, OAG and CPA were from Calbiochem (Nottingham, UK). Calphostin C, RHC-80267 and U-73122 were from Affinity Research (Exeter, UK). Stock solutions of calphostin C, CPA, OAG, PDBu, RHC80267 and U-73122 were all made using dimethyl sulphoxide (DMSO). Stock concentrations of BAY K 8644, nifedipine and ryanodine were made in ethanol. All subsequent dilutions were made in PSS and the final organ bath concentration of DMSO or ethanol never exceeded 0.001%. Both acetylcholine and norepinephrine were dissolved in water. PSS (composition in mmol): NaCl 119, KCl 4.5, NaHCO3 25, KH2PO4 1.0, MgSO4·7H2O 1.0, glucose 11 and CaCl2 2.5. K+ PSS composition (60 mm): equimolar substitution of NaCl with KCl otherwise identical to PSS. Ca2+ free PSS composition was identical to that of PSS other than the omission of CaCl2 and the addition of 1 mm EGTA.
2.5 Data and statistical analysis
Lumen diameters at each pressure step are presented as mean±S.E.M. Statistical analysis of the data was performed using GraphPad Prism software (San Diego, USA). Statistical comparisons of the maximum myogenic responses were performed using Student's t-test. One-way analysis of variance (ANOVA) for repeated measures, followed by Bonferroni test for multiple comparison, were used to compare pressure curve data. Statistical significance was assumed if P<0.05.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Myogenic tone
Following incubation in Ca2+ free PSS there was no significant difference in the luminal diameters of arteries at 40 mmHg when compared with luminal diameters in the presence of Ca2+ (Fig. 1). However, at 80 and 120 mmHg the luminal diameters were significantly smaller in the Ca2+ PSS when compared with the Ca2+ free PSS. There was a positive correlation between Ca2+-dependent myogenic tone and intraluminal pressure. Myogenic tone was calculated to be 5.5±1.1, 22.9±1.9 and 28.1±1.4% at 40, 80 and 120 mmHg, respectively (80 vs. 40 mmHg, P<0.01; 120 vs. 80 mmHg, P<0.05).
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3.2 Myogenic vasoconstriction response
In the presence of Ca2+ all arteries studied actively contracted in response to increasing intraluminal pressure. Table 2 shows the net myogenic vasoconstriction response across the two pressure steps studied (40–80 and 80–120 mmHg). The greatest myogenic contraction was consistently observed during the 40–80-mmHg pressure step. Although artery luminal diameter reduced in response to increasing the intraluminal pressure from 80 to 120 mmHg this was a significantly smaller contraction when compared with the myogenic-induced contraction observed during the 40–80-mmHg step (Table 2).
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3.3 Myogenic mechanisms
Table 2 shows the results of all the studies of the myogenic mechanisms represented as the net myogenic vasoconstriction response at each pressure step (i.e. 40–80 and 80–120 mmHg). Figs. 2–9
show the change in luminal diameter observed over the pressure steps.
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Incubation with nifedipine (1 and 10 µm) resulted in abolition of all myogenic responses in these arteries (Fig. 2). BAY K 8644 (10 nm) had little effect on myogenic responses, whereas, the higher concentration (100 nm) potentiated the myogenic response at 40–80-mmHg pressure step. However, BAY K 8644 failed to potentiate the myogenic response at the 80–120-mmHg pressure step (Fig. 3; Table 2).
The caffeine-induced release of Ca2+ from the SR and the subsequent vasoconstriction was reduced to 28.3±3.4% (P<0.01, n = 3) of the control response following incubation with ryanodine (10 µm) and 62.6±2.1% (P<0.01, n = 3) following incubation with CPA (10 µm). However, ryanodine or CPA had no effect on arterial basal tone or myogenic vasoconstriction (Fig. 4; Table 2).
Incubation with U-73122 (2 µm) significantly reduced the myogenic vasoconstriction response at 80 mmHg (Table 2, Fig. 5) and abolished the ability of the arteries to respond actively when the intraluminal pressure was increased from 80 to 120 mmHg. U-73122 had no effect on the K+-mediated vasoconstrictor or the PBDu response (data not shown).
Following incubation with the membrane permeable analogue of DAG, OAG (10 µm), the level of basal tone was marginally increased (Fig. 6) However, OAG did not modify myogenic responses (Table 2, Fig. 6) RHC-80267 (10 µm), a diacylglycerol lipase inhibitor, did not modify basal tone following the incubation period. RHC-80267 did however abolish myogenic responses at both pressure steps (Fig. 7).
Incubation with PDBu resulted in a concentration-dependent increase in basal tone (Fig. 8). In response to increasing the intraluminal pressure from 40 to 80 mmHg PDBu (10 and 30 nm) resulted in a significant increase in the myogenic vasoconstrictor response (Table 2). However, PDBu (10 or 30 nm) did not potentiate the myogenic response at the 80–120-mmHg pressure step. Incubation with calphostin C (30 and 100 nm) had no significant effect on basal tone at 40 mmHg (Fig. 9). Calphostin C (30 nm) did however significantly reduce the myogenic vasoconstriction response at the 40–80-mmHg pressure step (Fig. 9, Table 2) and abolished the myogenic vasoconstriction at the 80–120-mmHg pressure step. Increasing the concentration of calphostin C to 100 nm resulted in abolition of myogenic reactivity at both pressure steps (Fig. 9).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The signal-transduction mechanisms involved in the generation of myogenic tone are not established in human resistance arteries. In this study we have for the first time examined basic myogenic properties and identified the likely signal transduction mechanisms involved in the generation of myogenic tone in human subcutaneous resistance arteries. We have shown that the myogenic vasoconstriction in human subcutaneous arteries is associated with influx of extracellular Ca2+, via VOCCs, activation of PLC, diacylglycerol and subsequently PKC.
Myogenic vascular tone is reported to be a major determinant of blood flow and total peripheral resistance [1,22,23]. A number of animal studies have identified a positive correlation between resistance artery myogenic tone and hypertension [24,25]. However, whether this is a consequence or a cause of the hypertensive state remains to be elucidated. Identification of the mechanisms underlying myogenic tone may identify novel pharmaco-therapeutic interventions aimed at reducing the increased peripheral vascular resistance associated with certain hypertensive states.
The fundamental property of a resistance artery is to control fluctuations in blood pressure and modulate flow. To achieve this the resistance artery must constrict when blood pressure increases and dilate when blood pressure reduces. This present study has demonstrated that human subcutaneous arteries with a luminal diameter of 120 µm possess this fundamental property.
Ca2+ plays a central role in smooth muscle contraction. Numerous animal studies have identified that the vascular myogenic response is a Ca2+-dependent phenomenon [15,19,21,22,26]. In this study the myogenic response in human subcutaneous resistance arteries is similarly dependent on Ca2+. In a number of animal studies the source of Ca2+ has been shown to be from the extracellular environment [26,27]. In rat arteries the myogenic response is associated with membrane depolarisation, however, as yet, the event responsible for membrane depolarisation is as yet unidentified [1,5]. This response is abolished by dihydropyridines, therefore the likely pathway of Ca2+ entry is via VOCCs [13,15]. In this present study we observed similar findings as nifedipine abolished all myogenic responses. Conversely, activation of VOCCs with BAY K 8644 resulted in a potentiation of myogenic properties. It is likely that the action of BAY K 8644 on myogenic responsiveness to pressure is to increase the open state probability of VOCCs and thereby increase the sensitivity of smooth muscle to pressure-dependent increases in wall tension. However, BAY K 8644 only potentiated myogenic responsiveness at the 40–80-mmHg pressure step and was without further effect at the 80–120-mmHg pressure step. In this study the maximal myogenic vasoconstriction was consistently observed at the 40–80-mmHg pressure step. The fact that BAY K 8644 was unable to potentiate the myogenic response at the higher pressure step suggests that myogenic activity is greatest around 80 mmHg in human subcutaneous resistance. The inability of BAY K 8466 to further increase myogenic reactivity at the higher pressure step may reflect that VOCCs activity is maximal at the lower 40–80-mmHg pressure step. There are a number of ways in which VOCCs could participate in the myogenic response. Stretch-dependent increase in potassium channel and/or chloride channel activity has been implicated in initiating the depolarising event associated with VOCC activity and subsequently myogenic tone [1,11,12]. Likewise, PKC, shown to be involved in the generation of myogenic tone in cerebral arteries, has also been shown to directly modulate VOCC activity and indirectly modulate VOCC activity via potassium channel inhibition [28–32]. However, data from this present study offer no insight into the mechanism responsible for activation of VOCCs under these conditions.
Vasoconstrictor agonists have been shown to potentiate myogenic responses [15,33,34], suggesting that the transduction pathways involved in agonist-induced contraction and pressure-dependent myogenic contraction are similar [1]. This assumption has been confirmed in rat cerebral arteries where inhibition of PLC, an enzyme activated by adrenoreceptor agonists, attenuated myogenic reactivity [18]. PLC-dependent metabolism of membrane phospholipid is known to liberate both inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. In this study we have demonstrated a role for PLC in the generation of myogenic responses as the specific PLC inhibitor U-73122 had profound effects on this response. Similar observations have been reported in myogenically active rat cerebral arteries [17,18]. There is, however, evidence to suggest that U-73122 also has inhibitory effects on both VOCCs and SR Ca2+-ATPase pump [35]. With respect to the former we found that U-73122 had no effect on K+-mediated vasoconstriction. Therefore, we are confident that U-73122 at the concentration used in this study has no effect on VOCC function, although we cannot eliminate the possibility that U-73122 may inhibit SR function in this tissue. However, we have shown that the SR is unlikely to play any significant role in the generation of myogenic responses in these arteries and therefore any possible non-specific effect of U-73122 on SR function may not be relevant in this context.
There have been few studies that have specifically studied the role of SR and myogenic tone. The SR Ca2+ stores are involved in the myogenic response in rat skeletal muscle arteries [36]. In human subcutaneous resistance arteries we have confirmed, via the application of caffeine, that the SR stores release calcium. We have also demonstrated that they are likely to play no role in modulating myogenic responsiveness since both ryanodine or CPA were unable to modify the myogenic response. Ryanodine and CPA inhibit SR function through inhibition of the SR ryanodine receptor and the SR Ca2+-ATPase pump, respectively. Both ryanodine and CPA attenuated the caffeine-induced release of SR Ca2+ in these arteries, therefore we are confident both drugs were effective. Theoretically, inhibition of the SR's ability to buffer Ca2+ with ryanodine or CPA would increase [Ca2+]i and may have increased arterial myogenic reactivity or at least their sensitivity to pressure stimuli [37]. However, this assumption presupposes that the SR is important or directly involved in the generation of vascular tone per se in these arteries and specifically that the SR is involved in the generation of a pressure-dependent myogenic response. However, this may not be the case. Indeed, recently it has been shown that there is a correlation between SR volume and artery size, therefore SR function may be relatively unimportant in pressure-dependent responses in these small arteries [38].
Pressure-dependent distension of small arteries has been shown previously to stimulate PLC activity and the liberation of both diacylglycerol, an endogenous activator of PKC and IP3, a liberator of SR Ca2+ [39]. Our data suggest that the SR has no role in the mediation of the myogenic response under these ex-vivo conditions. Our data do however show a role for diacylglycerol, the co-product of IP3 following PLC-dependent phospholipid metabolism, as the diacylglycerol kinase inhibitor RHC-80267 completely inhibited the myogenic response. The diacylglycerol analogue OAG however had no effect on myogenic reactivity. This likely reflects that diacylglycerol activity is maximal as a consequence of pressure-dependent distension of the artery wall alone.
Myogenic reactivity being a diacylglycerol-dependent response is supported by the responses to pressure elevation in the presence of PDBu or calphostin C. These data confirm that the response is also PKC-dependent. A role for PKC in the myogenic mechanisms of vascular tone has previously been demonstrated in rabbit carotid, rat cerebral and human coronary arteries [17,18,40,41]. In this study the PKC activator PDBu and the specific PKC inhibitor calphostin C potentiated and attenuated the development of myogenic reactivity, respectively. Similar to the effects of BAY K 8644, the effect of the PKC activator PDBu was greatest at the 40–80-mmHg pressure step. Moreover, a 3-fold increase in the concentration of PDBu significantly increased basal tone along the pressure curve but did not increase pressure-dependent myogenic vasoconstriction. Again it is likely that the signal transduction mechanisms involved in the generation of myogenic vasoconstriction are maximally activated at the lower pressure step. Additionally, this observation indicates that the pressure-dependent Ca2+ influx event is greatest at the lower pressure step, however this is speculative and specific measurement of the Ca2+ influx would be required to confirm this. Moreover, these data offer no insight into the mechanism through which PKC acts.
In summary, this study has shown that human subcutaneous resistance arteries possess an intrinsic ability to respond myogenically to acute increases in intraluminal pressure. This study has also shown a positive association between intraluminal pressure and the development of myogenic tone. The generation of pressure-dependent myogenic tone is dependent on Ca2+ influx via VOCCs and a concomitant requirement for the activation of PLC, which in turn induces the activation of PKC, via diacylglycerol (Fig. 10).
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Time for primary review 26 days.
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