Published online before print June 7, 2007, doi: 10.1161/CIRCRESAHA.107.154443
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© 2007 American Heart Association, Inc.
Cellular Biology |
Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel
From the Institut de Pharmacologie Moléculaire et Cellulaire (N.B., O.P., S.M., V.G., M.L., C.H.), UMR6097, CNRS Université de Nice Sophia Antipolis, Institut Paul Hamel, Valbonne; Centre Commun de Microscopie Appliquée (P.G.), Université de Nice - Sophia Antipolis; Département de Pharmacologie Médicale (R.B.), EA 1046, Institut de Médecine Prédictive et de Recherche Thérapeutique (IMPRT), Faculté de Médecine de l’Université de Lille 2, Centre Hospitalier, Universitaire de Lille, Lille Cedex, France.
Correspondence to Catherine Heurteaux, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR 6097, Institut Paul Hamel, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France. E-mail heurteaux{at}ipmc.cnrs.fr
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Abstract |
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Vessel occlusion is the most frequent cause for impairment of local blood flow within the brain resulting in neuronal damage and is a leading cause of disability and death worldwide. Polyunsaturated fatty acids and especially
-linolenic acid improve brain resistance against cerebral ischemia. The purpose of the present study was to evaluate the effects of polyunsaturated fatty acids and particularly -linolenic acid on the cerebral blood flow and on the tone of vessels that regulate brain perfusion. -Linolenic acid injections increased cerebral blood flow and induced vasodilation of the basilar artery but not of the carotid artery. The saturated fatty acid palmitic acid did not produce vasodilation. This suggested that the target of the polyunsaturated fatty acids effect was the TREK-1 potassium channel. We demonstrate the presence of this channel in basilar but not in carotid arteries. We show that vasodilations induced by the polyunsaturated fatty acid in the basilar artery as well as the laser-Doppler flow increase are abolished in TREK-1–/– mice. Altogether these data indicate that TREK-1 activation elicits a robust dilation that probably accounts for the increase of cerebral blood flow induced by polyunsaturated fatty acids such as -linolenic acid or docosahexanoic acid. They suggest that the selective expression and activation of TREK-1 in brain collaterals could play a significant role in the protective mechanisms of polyunsaturated fatty acids against stroke by providing residual circulation during ischemia.
Key Words: cerebral ischemia • -linolenic acid • CBF • vasodilatation • two pore-domains channel TREK-1
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Introduction |
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After stroke, the function of cerebral arteries is critical to maintain cerebral perfusion and preserve neuronal integrity. The duration and intensity of the blood flow deficit are associated with the severity of brain damage. The level of cerebral blood flow (CBF) in brain tissue is coupled to an evident extent with vascular function and beyond neuronal consequences. It is well known that cerebral ischemia is associated with functional impairment of vascular tone within the occluded artery.1
Polyunsaturated fatty acids (PUFAs) and particularly -linolenic acid (ALA) and docosahexanoic acid (DHA) are potent protectors against focal and global ischemia.2–4 The molecular mechanism of PUFA-induced neuroprotection has been recently clarified.5 The main PUFA target seems to be the potassium channel, TREK-1, which belongs to the new family of two-pore domain potassium channels (K2P) and is known to be potently activated by PUFA.6–8 The importance of the TREK-1 channel in cerebral protection against ischemia has been validated by the fact that the protective effects of PUFA are drastically decreased in TREK-1–deficient mice.5
The vascular wall represents the primary compartment of ischemic stroke. PUFA application confers neuronal protection,2–4 but little is known about TREK-1 channel in cerebral vessels. A previous report shows the presence of the TREK-1 channel in mesenteric rat arteries but not in pulmonary arteries, suggesting that the expression pattern of this channel depends on the type of arteries.9 On the other hand, Bryan et al report the presence of K2P channels in vascular smooth muscle cells of rat middle cerebral arteries,10 and we have recently described the crucial role of the TREK-1 channel in both mesenteric arteries and skin microvessels.11 In these vessels the TREK-1 deletion leads to a dysfunction of endothelial factors production, particularly NO, that are responsible for smooth muscle relaxation.11 The aim of this work was to determine whether TREK-1 could also play a role in the cerebral circulation. We have addressed the following questions: (1) is there a crucial role for the TREK-1 channel in the cerebral vasculature, especially in the basilar artery? (2) could the PUFA-induced activation of vascular TREK-1 channels result in cerebral vasodilation, which would result into a protective mechanism?
This study examines the effect of PUFAs on cerebral laser-Doppler blood flow and vessel tone. It also analyzes TREK-1 distribution in different arteries and establishes with TREK-1–/– mice that the increased cerebral blood flow and vasodilation of basilar arteries produced by PUFAs is due to an action on TREK-1 channels.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement available at http://circres.ahajournals.org.
Artery Vasoreactivity
Dissected rat carotid arteries were quickly placed in ice-cold physiological saline solution (PSS), cut into ring segments of 2 to 3 mm length and mounted for standard tension-recording in isolated organ baths (Radnoti Glass Technology) containing 40 mL PSS bubbled with 95% O2/5% CO2. Then, carotid segments were equilibrated 30 minutes at 37°C, underwent a passive force normalization procedure to determine for each vessel a passive length-tension curve and the resting tension leading to optimal responses (8 mN/mm).12 Isometric tension was recorded with a force-displacement transducer connected to a data acquisition system (Workbench PC software).
Segments of dissected arteries of rats (basilar) and mice (basilar and carotid) were mounted in a small vessel arteriograph (LSI) on two glass cannulas, perfused13 with PSS equilibrated with 20% O2/5% CO2/balance N2, and maintained at 37°C and pH 7.4. Briefly, the proximal cannula was connected to a pressure transducer, a miniature peristaltic pump, and a servocontroller that continually measured and adjusted transmural pressure (TMP), and then the lumen diameter was analyzed in the no-flow condition through a camera coupled to a video dimension analyzer. Basilar arteries were equilibrated at a TMP of 75 mm Hg for 1 hour before experimentation, at which time basilar arteries spontaneously developed pressure-induced myogenic tone.
Responses to fatty acids were determined by successive additions of linolenic acid (ALA; 10, 100 µmol/L), docosahexanoic acid (DHA; 10, 100 µmol/L), and palmitic acid (PAL; 10 µmol/L) on both basilar and carotid arteries. The smooth muscle relaxation was assessed with sodium nitroprusside (SNP; 10 µmol/L) and papaverine (10 µmol/L), respectively, for active and passive relaxation. The smooth muscle constriction was tested with serotonin (5-HT; 1 µmol/L) for rat arteries and endothelin-1 (ET-1; 10 nmol/L) for mouse arteries. The mice endothelium-induced relaxing response was evaluated by acetylcholine (ACh; 10 µmol/L) application after preconstriction by ET-1 (10 nmol/L).
The PSS ionic composition was as follows (mmol/L): 119 NaCl, 24 NaHCO3, 4.7 KCl, 1.18 KH2PO4, 1.17 MgSO47H2O, 10 glucose, 1.6 CaCl2, pH 7.4. All fatty acid (Avanti Polar Lipids) and vasoactive drugs (ACh, ET-1, Papaverine, 5-HT, SNP, and KCl; Sigma-Aldrich) were made fresh daily as stock solutions of 0.1 mol/L and stored at 4°C.
Percent of dilation was calculated according to the following equation: [(Dfa-Db)/Index VC]*100, where D is the diameter on stabilization, after vehicle or fatty acid administrations (fa), baseline (b) and the index of vessel capability (VC index) is provided applying papaverine (10 µmol/L) on rat serotonin-precontracted vessels or mice endothelin-1–precontracted vessels. The VC index corresponds to the difference between the maximum diameter and the basal precontracted diameter.
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Are Fatty Acids Active on Rat Basilar Artery Tone?
Myogenic tone and vasoactive responses to serotonin (5-HT) or sodium nitroprusside (SNP) were indications of a viable basilar artery13,14 (data not shown). The fatty acid–induced relaxation was studied in arteries that possessed an intact endothelium equilibrated with 20% O2/5% CO2/balance N2 and maintained at 37°C and pH 7.4.
Alpha-linolenic acid (ALA) and docosahexanoic acid (DHA), which are known to potently activate the TREK-1 channel6,15 and which protect the brain against stroke,2 were tested (Figure 1). The 10-µmol/L and 100-µmol/L concentrations of ALA correspond to concentrations at which this PUFA is a potent activator of the TREK-1 channel.2 ALA induces an increase of the basilar artery diameter (Figure 1A). The maximal relaxation is of 54.8±8.9% at 100 µmol/L (n=10; Figure 1C). The relaxation induced by 100 µmol/L DHA was in the same range, at 42.9±9.7% (data not shown). At 10 µmol/L, ALA and DHA induced relaxations are 32.2±3.9% and 23.4±5.7%, respectively. Palmitic acid (PAL), a saturated fatty acid that does not activate the TREK-1 channel6–8,16 and does not protect neurons,2 had no effect on the basilar artery (Figure 1A and 1C). The basilar vasodilation induced by 10 or 100 µmol/L of ALA (30.9±3.1% and 38.2±6.8%, respectively) is not affected by the presence of NG-nitro-L-arginine (L-NNA, 10 µmol/L), a blocker of nitric oxide synthase,17 reflecting that ALA-induced vasodilation is mostly independent of the nitric oxide (NO) pathway. Because cyclooxygenase metabolites of PUFA, especially of arachidonic acid are vasoactive and generally potent dilators,18 we performed the same type of experiments on rat basilar artery in presence of L-NNA (10 µmol/L) and indomethacin (10 µmol/L) to inhibit both NO and prostanoids pathways. This treatment did not affect the relaxation induced by 10 µmol/L ALA (33.9±7.1%, n=7, data not shown).
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Are Fatty Acids Active on Rat Carotid Artery Tone?
Using a carotid segment, the main artery supplying blood, oxygen, and glucose to the brain, we analyzed whether this blood vessel also responds to ALA. ALA (10 µmol/L) was unable to dilate the carotid segment (n=10), and PAL (10 µmol/L) failed to produce relaxation (Figure 1B and C).
ALA Injection Induces Laser-Doppler Flow (LDF) Changes in MCA Territory
Laser-Doppler flowmetry was used for continuous estimation of hemodynamic changes in the cerebral microcirculation. The variation of the regional LDF in the rat MCA territory was measured 30 minutes after either a vehicle (n=6) or a 500 nmoles/kg ALA injection (Figure 1D). The dose of 500 nmoles/kg was selected based on our previous studies, where this dose offers the best protection against global ischemia.2,3 Although not statistically significant, LDF associated to MCA have a tendency to decrease in the 30 minutes after initial vehicle injection. During the experiment, normocapnia was not maintained by mechanical ventilation of the rat lungs and it is known that isoflurane tends to induce hypocapnia that could reduce global LDF up to 30%.19 The LDF of ALA-injected rats increased almost by 20% in the 30 minutes after injection. In all ALA-injected rats, a marked increase was noted as soon as 10 minutes after injection (data not shown). In our experiment, no significant difference in the continuous monitoring of mean arterial blood pressure was observed (data not shown).
TREK-1 Channel Distribution in Different Rat and Mouse Arteries Delivering Blood to Brain
We determined the presence of TREK-1 channels in the different rat and mouse arteries, which represent the 2 delivery pathways for cerebral blood flow. TREK-1 mRNA expression was assessed not only in rat basilar and carotid arteries (Figures 2 and 3
), that are relevant for stroke, but also in femoral artery as an independent control not related to brain perfusion (data not shown). RT-PCR experiments demonstrated the presence of mRNA encoding for TREK-1 only in basilar arteries (Figure 2A and 2B).
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Expression of the TREK-1 channel protein was also analyzed by Western blots using a well-characterized antibody.20 Under reducing conditions, in the presence of ß-mercaptoethanol (ß-Me), anti–TREK-1 antibodies labeled in the basilar artery a major band at approximately 45 kDa (Figure 2A and 2B) corresponding to the size predicted for the TREK-1 subunit.20 TREK-1 was hardly detectable in carotid (Figure 2A and 2B) and in femoral arteries (data not shown).
The subcellular location of TREK-1 mRNA was examined first by in situ hybridization in both basilar and carotid arteries. TREK-1 mRNA is expressed throughout the myocyte and the endothelial cell layer of the basilar artery (Figure 2C). TREK-1 mRNA is absent in the carotid and femoral arteries (not shown). Immunohistochemical labeling on basilar arteries sections (Figure 2C) indicated that TREK-1 expression was widespread throughout the basilar wall in both myocytes and endothelial cell layers. The TREK-1 channel was colocalized with antigen CD31 (also called platelet endothelial cell adhesion molecule[PECAM]), a specific marker of endothelial cells in blood vessels21 (Figure 2C, merged panel).
In mice arteries, TREK-1 mRNA was only present in basilar arteries (Figure 3A and 3B). The quantitation of the TREK-1 transcriptional expression showed that TREK-1 mRNA remained poorly detectable in carotid artery as compared with the basilar artery (P>0.001). Protein expression of TREK-1 by Western Blotting indicated a band of approximately 45 kDa corresponding to the predicted size of the TREK-1 protein. This band was only detectable in the basilar artery (Figure 3A and 3B).
Effects of Different Fatty Acids on Mouse Basilar and Carotid Arteries
As for rat arteries, mice basilar and carotid arteries were studied with an intact endothelium in PSS equilibrated with 20% O2/5% CO2/balance N2 and maintained at 37°C and pH 7.4. Vasoactive responses such as spontaneous contraction (myogenic tone), endothelin-1-induced contraction, and sodium nitroprusside–induced relaxation were assessed as indicative controls of the basilar viability in conditions of intraluminal pressure of 75 mm Hg13,14 (supplemental Table I). ALA or DHA at 10 µmol/L and 100 µmol/L induced a marked relaxation of the mice basilar artery, but not of the carotid artery (Figure 3C). As expected, palmitic acid (10 µmol/L) had no effect on these arteries. The maximal relaxation of the mouse basilar artery was reached at a concentration of 100 µmol/L ALA (62.1±6.8%), but this relaxation was not very different from that induced by 10 µmol/L ALA (41.9±7.2%; Figure 3C). DHA had a similar effect with a relaxation of 51.0±5.5% at 10 µmol/L and 45.3±3.5% at 100 µmol/L. SNP-induced relaxation was not statistically different between carotid and basilar arteries. As for the rat basilar artery, L-NNA treatment (10 µmol/L) did not modify the relaxation induced by 10 µmol/L ALA (48.3±4.6%, n=9) or 100 µmol/L ALA (62.4±10.8%, n=9) (Figure 3C).
Effects of Different Fatty Acids on Mouse Basilar Artery Tone in TREK-1+/+ and TREK-1–/– Mice
PUFA effects on mice basilar artery tone were then studied in wild-type and TREK-1 knock-out mice (TREK-1–/–). As before, vasoactive responses to pressure (myogenic tone) and to endothelin-1 (contraction) and sodium nitroprusside (relaxation) indicated the viability of the mouse mounted segments. They were not different in TREK-1+/+ and TREK-1–/– basilar arteries (supplemental Table I), indicating that the basic vascular properties were conserved in both genotypes. Supplemental Figure II shows that the endothelium is present and intact in basilar arteries of knock-out mice. Although treatment with 10 µmol/L and 100 µmol/L ALA increased the basilar diameter in TREK-1+/+ mice (Figure 4A), they had essentially no effect on the basilar artery of TREK-1–/– mice (Figure 4B). Palmitic acid was without effect on the diameter of both TREK+/+and TREK-1–/– arteries (Figure 4B). The basilar artery relaxation induced by 10 µmol/L and 100 µmol/L DHA was also markedly decreased if not abolished in TREK-1–/– vessels (Figure 4C). The lack of ALA or DHA-induced relaxation in vessels isolated from TREK-1–/– mice strongly suggests a central role of the TREK-1 channel in PUFA effects on basilar artery tone. A classical way to evaluate endothelium-mediated vasodilation is to use acetylcholine (ACh). Application of ACh on TREK-1+/+ basilar artery resulted in a relaxation of 65.3±6.4% (Figure 4D), which was classically decreased after L-NNA alone or L-NNA+indomethacin incubation (data not shown). In TREK-1–/– mice, the ACh-induced vasodilation was strongly attenuated (3.3±4.8%) (Figure 4D).
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Laser-Doppler Flow (LDF) Changes After PUFA Injection Are Linked to TREK-1
Figure 5 shows the LDF variation in the MCA territory of TREK-1+/+ and TREK-1–/– mice measured 30 minutes after either a vehicle or a 500 nmoles/kg ALA or DHA injection. TREK-1+/+ LDF associated with the MCA area statistically increased in the 30 minutes after initial ALA or DHA injection. Cerebrovascular reactivity to ALA (or LDF responses to PUFA) looked clearly different from those induced by standard vasodilator stimuli (acetazolamide and hypercapnia).22 This LDF increase occurred while the continuous monitoring of systolic blood pressure displayed no change after ALA injection in the TREK+/+ mice (supplemental Table II). Autoregulation depends on the ability of resistance vessels to dilate when mean arterial blood pressure (MABP) falls and to constrict when MABP rises. In our experiment the MABP did not change. In addition, blood flow in TREK-1–/– mice had a tendency to decrease in the 30 minutes after initial ALA or DHA injection, but this decrease was not statistically significant from the vehicle injection. In addition, CBF responses to ALA and DHA injections were drastically different in TREK-1+/+ and TREK-1–/– animals (###P<0.001) suggesting again a central role of the TREK-1 channel in PUFA effects on CBF regulation. As control, we also compared the MABP between TREK-1 KO and WT mice. There was no significant difference (TREK+/+ mice: 72.5±2.6 and TREK-1–/–: 73.1±2.9 mm Hg, n=6 per phenotype).
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Discussion |
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The purpose of this study was to gain more insight into the mechanism of PUFA-induced brain resistance to ischemic stroke. In ischemic stroke, the neurovascular unit is damaged primarily by the reduction of blood flow and the cerebral infarct size is inversely related to CBF. This paper reports for the first time the action of PUFAs on CBF as well as on cerebral arteries dilation, a property that may be related to their protective effects against brain ischemia.2–4 LDF-monitoring has shown that an acute injection of ALA significantly increases the local cerebral blood flow in the rat MCA area. This
20% increase of the flow is related to an increased vasodilation. Indeed, ALA acts as a vasoactive compound and leads to a 30% increase of the diameter of the basilar artery. This effect appears to be specific to cerebral resistance arteries, because ALA does not dilate carotid arteries with elastic properties. The results are consistent with the idea that ALA induces vasodilation only in resistance arteries such as those of the cerebral vascular bed, without decreasing systemic blood pressure. A vasoactive effect in the basilar artery is also observed with the other classical polyunsaturated fatty acid DHA, whereas it is not seen with a saturated fatty acid such as PAL. We propose that the increased capacity of brain arteries to dilate after PUFA treatment increases collateral flow, reduces CBF loss in the periphery of the ischemic zone, and contributes to the PUFA-induced protection against ischemic stroke. Improved collateral flow might lead to an increase of cerebral tissue perfusion especially in the penumbra and might limit the spread of the infarct. The TREK-1 channel has been previously demonstrated to be involved in the ALA-induced resistance of the brain against ischemia.5 This channel is a member of the family of potassium channels with two pore-forming domains having the properties of background K+ channels.6–8 This channel is potently activated by PUFAs such as ALA and DHA, but not by the saturated fatty acid PAL.23 Recent work has provided evidence for the presence of two-pore domain K+ channels in rat mesenteric, cerebral, and pulmonary arteries, suggesting that some of these channels could play a physiological role in regulating basal membrane potential and tone in these vessels.9,10,24 This article shows that TREK-1 channels are well expressed in the basilar vasculature of both rats and mice whereas they are essentially absent in the carotid artery. There is a strict parallelism between the localization of TREK-1 channels in these different arteries and the vasodilation effect of PUFAs, which is observed only with basilar but not carotid arteries. This work supports the idea that TREK-1 plays an important role in the vasodilator responses to PUFAs. Indeed, the lack of PUFA-induced vasodilation in TREK-1–/– mice indicates clearly that PUFA-induced relaxation on arterial basal tone is related to their action on the TREK-1 channel.
Our laboratory has recently shown an important effect of TREK-1 deletion on microvascular function in mesenteric arteries and skin microvessels.11 Acetylcholine, bradykinin, and cutaneous pressure-induced vasodilation were drastically altered in mice lacking the TREK-1 channel. Deletion of the TREK-1 channel was shown to be associated with an impairment in the cascade producing NO, leading to endothelial dysfunction.11 In cerebral basilar arteries, the deletion of TREK-1 does not alter smooth muscle vasodilation in response to the NO-donor SNP, but it abolishes the response to ACh. These new observations are in line with our previous work.11 They indicate an impairment of endothelial function in TREK-1–/– mice basilar arteries. Thus, to gain insight into the mechanism by which TREK-1 deletion alters PUFA-induced relaxation, we first investigated the hypothesis of a NO pathway alteration in the TREK-1–/– mice. If PUFA-induced vasorelaxation only relies on NO production by the endothelial cell, then L-NNA, an inhibitor of NO synthase, should drastically decrease ALA- or DHA-induced vasodilation of basilar arteries. This is not what we have observed, suggesting the involvement of an NO-independent mechanism in the vasorelaxation process. To ensure that prostanoids, which are also important regulators of vascular tone, were not responsible for the observed vasodilation, we also combined L-NNA and indomethacin, a nonselective inhibitor for cyclooxygenases. This treatment again did not alter ALA- or DHA-induced vasodilation of basilar arteries. PUFA-induced vasodilation of cerebral vessel is a non–NO-dependent and non–prostanoid-dependent mechanism. This result leaves us with 2 possible mechanisms to explain PUFA-induced vasodilation in relation with TREK-1 channels. The first one would involve an endothelial component, distinct from NO and prostanoids, which could be EDHF.25 The second one would involve a direct effect of PUFAs on smooth muscle creating an hyperpolarizing-relaxing response. Bryan et al10 have recently demonstrated the presence of an "atypical" K+ channel, insensitive to classical potassium channels inhibitors, with biophysical properties similar to K2P channels of the TREK-1 family, that, in response to arachidonic acid, hyperpolarizes smooth muscle and dilates MCA artery.10
The NO-independent PUFA-induced vasodilation reported here is a particularly interesting observation considering the drastic alteration of endothelium-dependent NO-mediated vasodilation in cerebral arteries after stroke.26,27 The consequence of ALA- and DHA-mediated vasodilation is an increased LDF. We have previously demonstrated a neuronal protection induced by PUFA treatment in models of ischemia.4,5 In a model of focal ischemia, the ALA treatment was found to be efficient to protect from ischemic damage up to 6 hours after reperfusion, ie, within a clinically interesting time window. The beneficial effects of ALA have been reported to be attributable in part to its activating effect on neuronal TREK-1 channel, preventing an excessive release of excitotoxic glutamate and favoring a Mg2+ block at postsynaptic NMDA receptors.2 This article indicates that the protection is potentially also attributable to ALA-induced vasodilation, also via TREK-1 channels. In the pathobiology of ischemic stroke, anoxic depolarization and periinfarct spreading depression are 2 major events that have been linked to worsening focal ischemic damage.1 The reduction of oxygen delivery in both core and penumbra is attributable to the additional metabolic burden imposed on the ischemic brain but also to the ischemic depolarization consequences on the brain vascular network causing vasoconstriction. This secondary reduction in CBF probably expands the infarct during stroke. PUFA activation of TREK-1 channels would be expected to generate resistance to depolarization of the collateral vessels and lead to a better tissue oxygenation during acute focal cerebral ischemia and reperfusion. PUFAs would be expected to increase the resistance to vasoconstriction induced by ionic changes produced by the depolarization wave, leading to spreading ischemia.28 We did not examine the role of this channel in CBF autoregulation reflecting the fundamental property of the cerebral circulation that enables it to maintain stable brain perfusion in face of blood pressure changes.
To our knowledge, this work is the first demonstration that the TREK-1 channel is involved in the control of brain circulation and that PUFAs that are so popular (particularly omega-3s) in preventive automedication29,30 have a beneficial effect on brain blood flow via this particular type of channel.
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Acknowledgments |
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The authors are grateful to Drs F. Lesage for the gift of the TREK-1 antibody, to N. Guy for production of TREK-1–deficient mice, to Dr J. Mazella for his helpful advice for the Western blotting, and to Dr M. Popolo for her comments on the manuscript. We also thank C. Widmann, G. Jarretou, C. Gandin, and Y. Benhamou for their helpful assistance.
Sources of Funding
This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut Paul Hamel, and the Fondation Coeur et Artères. Dr O. Pétrault was the recipient of a LEEM Recherche Fellowship.
Disclosures
None.
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Footnotes |
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*Both authors contributed equally to this study.
Original received February 2, 2006; resubmission received April 18, 2007; revised resubmission received May 22, 2007; accepted May 30, 2007.
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References |
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1. Dirnagl U, Iadecola C, Moskowitz M. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999; 22: 391–397.[CrossRef][Medline] [Order article via Infotrieve]
2. Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M. Polyunsaturated fatty acids are potent neuroprotectors. EMBO J. 2000; 19: 1784–1793.[CrossRef][Medline] [Order article via Infotrieve]
3. Blondeau N, Widmann C, Lazdunski M, Heurteaux C. Polyunsaturated fatty acids induce ischemic and epileptic tolerance. Neuroscience. 2002; 109: 231–241.[CrossRef][Medline] [Order article via Infotrieve]
4. Heurteaux C, Laigle C, Blondeau N, Jarretou G, Lazdunski M. Alpha-linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia. Neuroscience. 2006; 137: 241–251.[CrossRef][Medline] [Order article via Infotrieve]
5. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G, Lazdunski M. TREK-1, a K(+) channel involved in neuroprotection and general anesthesia. EMBO J. 2004; 23: 2684–2695.[CrossRef][Medline] [Order article via Infotrieve]
6. Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, Lazdunski M. A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acid. EMBO J. 1998; 17: 3297–3308.[CrossRef][Medline] [Order article via Infotrieve]
7. Lesage F, Lazdunski M. Molecular and functional properties of two pore domain potassium channels. Am J Physiol. 2000; 279: 793–801.
8. Patel AJ, Honore E. Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci. 2001; 24: 339–346.[CrossRef][Medline] [Order article via Infotrieve]
9. Gardener MJ, Johnson IT, Burnham MP, Edwards G, Heagerty AM, Weston AH. Functional evidence of a role for two-pore domain potassium channels in rat mesenteric and pulmonary arteries. Br J Pharmacol. 2004; 142: 192–202.[CrossRef][Medline] [Order article via Infotrieve]
10. Bryan RM, Jr., You J, Phillips SC, Andresen JJ, Lloyd EE, Rogers PA, Dryer SE, Marrelli SP. Evidence for two-pore domain potassium channels in rat cerebral arteries. Am J Physiol Heart Circ Physiol. 2006; 291: H770–H780.
11. Garry A, Fromy B, Blondeau N, Henrion D, Brau F, Gounon P, Guy N, Heurteaux C, Lazdunski M, Saumet JL. Altered acetylcholine, bradykinin and cutaneous pressure-induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link. EMBO Rep. 2007; 8: 354–359.[CrossRef][Medline] [Order article via Infotrieve]
12. Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977; 41: 19–26.
13. Petrault O, Ouk T, Gautier S, Laprais M, Gele P, Bastide M, Bordet R. Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion. Br J Pharmacol. 2005; 144: 1051–1058.[CrossRef][Medline] [Order article via Infotrieve]
14. Bai N, Moien-Afshari F, Washio H, Min A, Laher I. Pharmacology of the mouse-isolated cerebral artery. Vascul Pharmacol. 2004; 41: 97–106.[CrossRef][Medline] [Order article via Infotrieve]
15. Lesage F, Lazdunski M. Potassium channels with two P-domains. In: Kurachi Y, Jan LY, Lazdunski M, eds. Potassium Ion Channels. Molecular Structure, Function, and Diseases - Current Topics in Membranes. Vol 46. San Diego, CA: Academic Press; 1999: 199–222.
16. Patel A, Lazdunski M, Honore E. Lipid and mechano-gated 2P domain K(+) channels. Curr Opin Cell Biol. 2001; 13: 422–428.[CrossRef][Medline] [Order article via Infotrieve]
17. Reif DW, McCreedy SA. N-nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases. Arch Biochem Biophys. 1995; 320: 170–176.[CrossRef][Medline] [Order article via Infotrieve]
18. Campbell WB, Harder DR. Endothelium-derived hyperpolarizing factors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone. Circ Res. 1999; 84: 484–488.
19. Young WL, Barkai AI, Prohovnik I, Nelson H, Durkin M. Effect of PaCO2 on cerebral blood flow distribution during halothane compared with isoflurane anaesthesia in the rat. Br J Anaesth. 1991; 67: 440–446.
20. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honore E. TREK-1 is a heat-activated background K(+) channel. EMBO J. 2000; 19: 2483–2491.[CrossRef][Medline] [Order article via Infotrieve]
21. Ilan N, Madri JA. PECAM-1: old friend, new partners. Curr Opin Cell Biol. 2003; 15: 515–524.[CrossRef][Medline] [Order article via Infotrieve]
22. Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A. Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke. 2005; 36: 1053–1058.
23. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E. Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. J Biol Chem. 2000; 275: 10128–10133.
24. Gurney A, Osipenko O, MacMillan D, McFarlane K, Tate R, Kempsill F. Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle. Circ Res. 2003; 93: 957–964.
25. Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: bringing the concepts together. Trends Pharmacol Sci. 2002; 23: 374–380.[CrossRef][Medline] [Order article via Infotrieve]
26. Seal J, Gewertz B. Vascular dysfunction in ischemia-reperfusion injury. Ann Vasc Surg. 2005; 19: 572–584.[CrossRef][Medline] [Order article via Infotrieve]
27. Aliev G, Obrenovich M, Seyidova D, de la Torre J. Exploring ischemia-induced vascular lesions and potential pharmacological. Histol Histopathol. 20: 261–273, 2005.[Medline] [Order article via Infotrieve]
28. Windmuller O, Lindauer U, Foddis M, Einhaupl K, Dirnagl U, Heinemann U, Dreier J. Ion changes in spreading ischaemia induce rat middle cerebral artery. Brain. 2005; 128: 2042–2051.
29. Leaf A, Kang J, Xiao Y, Billman G, Voskuyl R. The antiarrhythmic and anticonvulsant effects of dietary N-3 fatty acids. J Membr Biol. 1999; 172: 1–11.[CrossRef][Medline] [Order article via Infotrieve]
30. Bourre JM. Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing. J Nutr Health Aging. 2004; 8: 163–174.[Medline] [Order article via Infotrieve]
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