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Departments of 1 Physiology2 Pharmacology, University of Birmingham, Birmingham B15 2TT, UK
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(Received 10 August 2004;
accepted after revision 4 October 2004; first published online 4 October 2004)
Corresponding author T. A. Lovick: Department of Physiology, The Medical School, University of Birmingham, PO Box 363, Vincent Drive, Birmingham B15 2TT, UK. Email: t.a.lovick{at}bham.ac.uk
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Introduction |
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There are several indications that the process is multivariate. Nitric oxide and adenosine have already been identified as important mediators of the coupling process (Li & Iadecola, 1994; Hiff et al. 2003). More recent evidence suggests that vasodilator substances derived from astrocytes may also be involved. Astrocytic processes engulf synapses and are able to detect changes in the release of glutamate and other neurotransmitter substances (Pasti et al. 1997). In addition, astrocytic end-feet lie in close apposition to cerebral blood vessels (Ramon y Cajal, 1952; Simard et al. 2003) and recent studies have shown that mechanical stimulation of astrocytes can evoke dilatation of nearby arterioles (Zonta et al. 2003). It has been suggested that release of dilator substances from atrocytic end-feet may contribute to the hyperaemic response (Harder et al. 2000). Astrocytes metabolize arachidonic acid via the enzymatic epoxygenation of fatty acid to epoxyeicosatrienoic acids (EETs), several of which have potent vasodilator actions (Gebremedhin et al. 1992; Amruthesh et al. 1993). Studies in vivo have indicated that the release of EETs may contribute to the hyperaemic response following NMDA receptor activation (Bhardwaj et al. 2000) and may also provide a background level of dilator tone within the cerebral circulation (Alkayed et al. 1996a). However, this latter finding has not been confrmed (Peng et al. 2002) and it is possible that the use of different anaesthetic agents in these studies may be a confounding factor. In addition to their presence in astrocytes, EETs have been detected in cerebrovascular endothelial cells (Medhora et al. 2001). The endothelium may therefore be another source of EETs that contributes to the regulation of cerebrovascular tone.
In the present study we have investigated the role of epoxygenase products in activity-related dilatation in brain slices. In this preparation the responses of individual microvessels can be observed directly in situ within the neuropil. More importantly, these studies can be conducted in the absence of anaesthetic agents which may influence the responsiveness of cerebral blood vessels in those studies carried out in vivo. Astrocytes express the 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. They respond to this agonist with an increase in intracellular Ca2+, which is propagated as a wave and travels between neighbouring cells via gap junctions (Carmignoto, 2000). In the present study we have used AMPA to stimulate astrocytes (and neurones) and investigated the role of epoxygenase products in mediating vasodilator responses evoked in intraparenchymal cortical arterioles.
In a previous study we found that arterioles in hippocampal brain slices, which had been preconstricted with a vasoconstrictor agent, developed rhythmic contractile activity (vasomotion; Brown et al. 2002a). This activity ceased when the vessels dilated during periods of increased synaptic activity. Inhibition or a reduction of vasomotion, together with the increase in intraluminal diameter, may therefore contribute to the hyperaemic response. However, vessels within the in situ slice preparation, although possessing luminal contents, were not perfused. Thus myogenic tone, induced in response to the hydrostatic pressure (Ward et al. 2000) normally exerted by the circulating blood, would be negligible or absent. In this respect the preparation does not faithfully reproduce the normal physiological condition. Thus, as a preliminary to the main part of this study, it was necessary to establish whether or not vasomotion was related to the increase in vascular tone rather than being a direct pharmacological response to the exogenous constrictor agent used in this study. We therefore cannulated a number of cerebral arterioles in situ in slices of cortex and observed their responses when infused with artificial cerebrospinal fluid to pressurize the vessel.
Parts of the work have been published in abstract form (Brown et al. 2002b; Lovick et al. 2003).
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All drugs for this study were obtained from Sigma. AMPA (1 µM), tetrodotoxin (1 µM) and U46619 [GenBank] (75 nM) were dissolved in ACSF, whilst miconazole was initially dissolved in ethanol and then diluted further to give a final concentration of 20 µM in 0.001% ethanol in ACSF. At this concentration, miconazole has been shown to inhibit formation of EETs selectively in astrocytic cultures (Alkayed et al. 1996). Values are expressed as means ± S.E.M. Changes in internal diameter and the frequency of vasomotion were analysed by ANOVA or Student's paired two-tailed t test as appropriate, using the raw data and with significance set at the 0.05 level.
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Results |
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Because of the elasticity and mobility of the arterioles within the slice, the cannulation procedure proved difficult. The procedure was attempted on 21 vessels. In 13 vessels cannulation was unsuccessful, since attempting to insert the pipette through the vessel wall produced detachment of the arteriole from the surrounding neural tissue for 70–200 µm downstream from the point of contact. In such vessels, which were dilated and quiescent prior to the attempted cannulation, their subsequent separation from the surrounding tissue induced a 26.8 ± 4.5% reduction in internal diameter and rhythmic contractions developed locally at a rate of 11.2 ± 1.1 min–1. However, 200–300 µm downstream, where the arteriole remained in contact with the surrounding tissue, the vessel remained dilated and exhibited little or no vasomotion.
Cannulation with minimal or no damage to the surrounding tissue was successful in eight cases. Insertion of the pipette tip was immediately followed by a –22.4 ± 3.7% constriction of the vessel around and within the vicinity of the cannula tip and vasomotion (9.8 ± 1.5 contractions min–1) was initiated locally. These changes were probably due to the physical presence of the cannula within the vessel, since the arterioles remained quiescent and dilated 100–300 µm both upstream and downstream from the site of cannulation. However, 2–30 min after commencement of the ACSF infusion the internal diameter of these segments also decreased and vasomotion was induced as the vessel constricted along its entire visible length (Fig. 1A and B). Infusion rates ranging from 0.1 to 20 µl min–1 were tried in order to find a rate sufficient to induce a level of fluid pressure within the vessel whilst producing minimal flow. The higher infusion rates (>5 µl min–1) invariably resulted in constriction followed by the gradual distension of the arteriole in excess of the initial resting diameter. In these arterioles, which had retained their luminal contents, it is likely that inadequate drainage from the vessel through the capillary bed to the cut surface of the slice led to a build up of excessive back pressure within the lumen. To surmount this problem the infusion rate was kept very low and the pressure allowed to build up gradually so that, as no distension occurred, the input presumably matched the leakage rate. A rate of 0.2 µl min–1 was judged to produce optimal responses for all vessels, indicating that very little fluid was necessary to prime the vessels. In six vessels in which cannulation had already produced an initial constriction and vasomotion, perfusion at 0.2 µl min–1 was followed by a further decrease in internal diameter and increase in the frequency of vasomotion (Figs 1A and B and 2), which developed within a 30 min period and thereafter remained relatively constant over the 1–1.5 h experimental period.
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The technical difficulties associated with cannulation and infusion of vessels in situ within the neuropil precluded the use of this technique as a routine procedure. Thus, in all further experiments, vascular tone was induced by the addition of an exogenous constrictor agent. A total of 23 arterioles with a mean diameter of 10.1 ± 0.7 µm were preconstricted by the addition of the thromboxane A2 agonist U46619 [GenBank] (75 nM) to the ACSF superfusing the slice. All vessels started to constrict within 2–5 min and the internal diameter achieved a stable level (mean decrease –14.2 ± 2.0%) below their resting diameter within 15 min. Vasomotion was initiated in quiescent vessels (5.31 ± 0.8 contractions min–1, n = 12). The remaining 11 vessels initially showed a low level of spontaneous activity that increased further in the presence of U46619 [GenBank] , from 6.34 ± 0.8 to 9.16 ± 0.9 contractions min–1.
Activity-related dilatation in cortical arterioles: response to a glutamate agonist
In five vessels preconstricted with 75 nM U46619 [GenBank] addition of AMPA (1 µM for 5 min) induced a 15.4 ± 3.7% (P = 0.002) increase in internal diameter (Fig. 1F and G) and either a significant reduction in the frequency (n = 3) or cessation (n = 2) of vasomotion (mean change –6.7 ± 1.4 contractions min–1, P < 0.01). On washout of the AMPA the internal diameter and rate of vasomotion returned to control values within 20 min (Fig. 1H). In a further five vessels 1 µM tetrodotoxin (TTX) was added to the ACSF (with 75 nM U46619 [GenBank] ) superfusing the slice. The inclusion of TTX produced no significant change in either the internal diameter (from 7.9 ± 0.8 to 8.0 ± 0.7 µm) or the rate of vasomotion (from 5.6 ± 1.3 to 5.4 ± 1.2 contractions min–1) of these vessels. The vasorelaxant effects of a 5 min application of 1 µM AMPA also persisted in the presence of TTX, in that the internal diameter still showed a significant increase (8.6 ± 0.9%, P < 0.003) and vasomotion decreased to 2.4 ± 1.0 contractions min–1 (P = 0.003). However, compared to the control, the response evoked in the presence of TTX was reduced. On washout, values returned to pre-AMPA levels within 20 min.
Effects of miconazole on vascular tone
In six vessels already preconstricted with U46619 [GenBank] (internal diameter 7.4 ± 1.1 µm, vasomotion 7.0 ± 1.0 contractions min–1), the addition of the epoxygenase inhibitor miconazole (20 µM) produced an additional –15.7 ± 5.9% decrease in the internal diameter as well as a further increase of +4.7 ± 1.3 contractions min–1 in the frequency of vasomotion. We were concerned that even small movements of the intraluminal fluid, due to the increased level of vasomotion within these highly preconstricted vessels, might have produced shear stress on the endothelial lining at a sufficient level to stimulate a tonic release of vasoactive agents from the endothelium. Since epoxygenases are present in cerebrovascular endothelium as well as in astrocytes (Medhora et al. 2001) and there is evidence that agents, such as NO, which are released in response to shear stress (Fissthalmer et al. 2000) may interfere with epoxygenase activity (Bauersadis et al. 1997), it would be difficult under these circumstances to determine the origin of the constrictor effect of miconazole. Thus, in order to minimize shear stress on the vessel wall, the application of miconazole was repeated in seven vessels that had not been preconstricted with U46619 [GenBank] . Initially these vessels were dilated and were either quiescent or showed a very low rate of spontaneous vasomotion (mean 3.0 ± 1.3 contractions min–1). However, in each vessel, the addition of miconazole produced a significant decrease in the internal diameter (–22.8 ± 5.2%, P = 0.007) and vasomotion was either initiated (n = 3), or in the others (n = 4) the rate increased to a mean of 8.6 ± 1.5 contractions min–1 (P = 0.05) for the group.
Effects of miconazole on brief AMPA-evoked dilatation. Since addition of miconazole to vessels already preconstricted with U46619 [GenBank] induced further constriction and increased the frequency of vasomotion, the baseline against which the effects of AMPA could be tested was not comparable to that using U46619 [GenBank] alone. In order to match baseline values, the effect of miconazole was assessed on a further four vessels without preconstriction with U46619 [GenBank] . Baseline values for internal diameter (9.6 ± 2.9 µm) and frequency of vasomotion in these miconazole-treated vessels were not significantly different from the group pretreated with U46619 [GenBank] . Interestingly, in these vessels a short (5 min) application of 1 µM AMPA still produced a significant increase in blood vessel diameter (26.6 ± 10.2%, P = 0.04) and reduced vasomotion from 10.7 ± 1.8 to 0.8 ± 0.5 contractions min–1 (P = 0.02).
Effects of miconazole on sustained AMPA-evoked dilatation. A further series of experiments was carried out to measure the stability of the AMPA-evoked dilatation in the presence of miconazole when assessed over a longer time period. A total of 14 slices were divided into two equal groups. Vessels in group 1 were preconstricted by superfusion with ACSF containing 75 nM U46619 [GenBank] . The internal diameter and rate of vasomotion were measured over a 30 min period before a further 30 min application of 1 µM AMPA followed by washout and recovery. In group 2 the protocol was identical except that miconazole (20 µM) replaced the U46619 [GenBank] in the perfusing solution.
In group 1 the application of U46619 [GenBank] produced a decrease in the internal diameter (–12.8 ± 2.5%, P = 0.02) and an increase in vasomotion (+5.0 ± 1.4 contractions min–1, P = 0.02; Fig. 3A) comparable to that seen in the earlier experiments. These changes became apparent within 2–5 min, became maximal within 10–15 min and remained stable for the rest of the 30 min drug application period. The addition of AMPA to the superfusate produced dilatation of the arterioles (i.d. increase +12.1 ± 1.5%, P = 0.02) and a reduction in the frequency of vasomotion (–8.4 ± 1.7 contractions min–1, P = 0.003), which began within 2–5 min of drug application and became maximal after 5–10 min. These changes were then maintained without significant decrement for the duration of the drug application period. The effects of AMPA were reversed on washout, all measurements returning to baseline levels by 20 min (Fig. 3). In vessels in group 2, superfusion with miconazole produced a decrease in the internal diameter of the arterioles (–11.1 ± 2.5%, P = 0.008) and an increase in vasomotion (+6.7 ± 0.8 contractions min–1, P = 0.0001) comparable to that seen with U46619 [GenBank] (Fig. 3). As with U46619 [GenBank] these changes, which also began within the first 2–5 min of drug application, were maintained throughout the initial 30 min perfusion period. Similarly, addition of AMPA (1 µM) to the perfusate produced equivalent degrees of vasodilatation (+9.8 ± 3.1%, P = 0.003, Fig. 3A) and reductions in vasomotion (–6.6 ± 1.5 contractions min–1, P = 0.003, Fig. 3B) within the same time scale. However, this dilator response was not maintained. After 10–15 min of superfusion with 1 µM AMPA the arterioles gradually began to contract and the rate of vasomotion began to increase, such that by the end of the 30 min drug application period all values had returned to, or near to, pre-AMPA levels (Fig. 3). Washout of AMPA produced no further changes.
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Discussion |
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However, the technique proved to be difficult. Firstly, it was necessary to find adequate lengths of arteriole within the same focal plane in order to observe the vessel at a distance from the point of cannulation. Secondly, even when this criterion was fulfilled, successful cannulation of these small vessels without significant adjacent tissue damage was achieved in only 15% of attempts. An alternative strategy was therefore employed. Myogenic tone was induced in non-cannulated vessels by the exogenous addition of the thromboxane A2 constrictor agent U46619 [GenBank] . The vasoconstriction induced by this agent was invariably accompanied by the development of rhythmic contractile activity. The fact that these contractions persisted in the presence of TTX would suggest that they were independent of on-going synaptic activity and represent a physiological property of the cerebrovascular smooth muscle cells in response to increases in myogenic tone.
Increasing myogenic tone by addition of U46619 [GenBank] proved successful in 98% of experiments. Moreover, stimulation of neuronal activity by the addition of the glutamate agonist AMPA produced dilatation and reduced or abolished the rhythmic contractile activity of these preconstricted intraparenchymal arterioles. We have previously shown that inhibition of vasomotion contributes to the activity-induced hyperaemic response of hippocampal arterioles maintained in situ in brain slice preparations (Brown et al. 2002a). The results of the present study would suggest that cortical arterioles respond in a similar manner.
Vasodilatation and inhibition of vasomotion induced by brief application of AMPA persisted in the presence of TTX, indicating that the response was independent of action potential generation. However, the amplitude of the response was reduced, suggesting that there is a TTX-sensitive component. In contrast, TTX has been reported to block almost completely the dilatation of arterioles evoked by the glutamate agonist NMDA (Fergus & Lee, 1997; Lovick et al. 1999). AMPA receptors are present on somatodendritic and terminal sites on neurones, as well as on astrocytes, whereas NMDA receptors are localized predominantly on neurones (Teichberg, 1991). The TTX-resistant component of the AMPA-evoked response may therefore represent the effect of predominantly astrocytic activation. Superfusion of AMPA at the relatively high concentration used in the present study might also have been expected to produce neurotoxic effects (Fowler et al. 2003). However, we found that activation of AMPA receptors for 30 min produced a dilator response that was similar in magnitude to the response evoked by a brief 5 min stimulus and, importantly, the response was maintained without decrement during this period. This suggests that no functional desensitization occurred.
In the presence of the epoxygenase inhibitor miconazole, arterioles already preconstricted with U46619 [GenBank] showed a further constriction and an increase in the frequency of vasomotion, suggesting that miconazole was blocking a tonic dilator influence within the tissue. At the dose level used, miconazole has been shown to inhibit formation of EETS selectively in astrocytic cultures (Alkayed et al. 1996b). In addition to astrocytes, EETs are also synthesized by vascular endothelial cells (Medhora et al. 2001). These cells could also provide a primary source of EETs in preconstricted vessels, where movement of intraluminal contents due to the induced vasomotion might provide a level of shear stress sufficient to stimulate tonic release of EETs. However, the fact that miconazole produced constrictor effects in quiescent, resting vessels suggests that the tonic release of EETs was from a source other than blood vessel endothelial cells. The most likely scenario is that miconazole was blocking the production of EETs from arachidonic acid within the surrounding astrocytes and thereby reducing tonic release from the astrocytic end-feet in intimate contact with cerebral vascular smooth muscle cells. In this context it is interesting to note that blood vessels that became detached from the surrounding neuropil during attempted cannulation procedures became constricted and spontaneously developed vasomotion. Constriction and vasomotion were not apparent away from the site of cannulation where contact with the surrounding neuropil was maintained.
The present results suggest that there is a tonic release of EETs from astrocytes that contributes to the maintenance of vascular tone within the cerebral circulation. These findings are in accordance with the results of previous in vivo studies, in which local blood flow was found to decrease following administration of miconazole into the subdural space (Alkayed et al. 1996a) or into the striatum (Bhardwaj et al. 2000). However, the findings were not replicated in another study in vivo (Peng et al. 2002), although it is possible that the use of different anaesthetic agents in these studies may be a confounding factor. During persistent neuronal activity in vivo, activity-related dilatation may be sustained over long periods of time. In the present study the AMPA-evoked dilatation was maintained without decrement over a 30 min application period. This suggests that AMPA receptors that initiated the cascade of events leading to release of dilator agents did not desensitize. However, when AMPA was applied for a 30 min period in the presence of miconazole, the later phase of the dilator response had become significantly attenuated after 10 min. The failure of miconazole to block the early phase of the response cannot be explained by insufficient tissue concentrations of miconazole, since application of the drug had already produced a decrease in resting diameter of vessels and an increase in the frequency of vasomotion. Rather, the results suggest that epoxygenase activity is not a prerequisite for the initial stage of neuronal activity-evoked dilatation.
Previous studies in vivo have indicated that, in addition to EETs, several other factors contribute to functional hyperaemia within the brain. Adenosine, extracellular ions, nitric oxide and cyclooxygenase 2 reaction products may all be involved (Akgören et al. 1994; Li & Iadecola, 1994; Iadecola et al. 1995; Caesar et al. 1999; Niwa et al. 2000; Hiff et al. 2003; Zonta et al. 2003). Of these, NO is a strong candidate for a primary mediator of neurovascular coupling. Local blood flow increases within 200 ms of an increase in neuronal activity (Nielsen & Lauritzen, 2001). The initial phase, which is delayed and reduced by inhibitors of nitric oxide synthase (Akgören et al. 1996; Yang & Iadecola, 1997), may be mediated in part by activation of the network of nitric oxide synthase-containing nerve fibres which permeate the neuropil (DeFelipe, 1993; Lovick et al. 1999) and release NO in close proximity to arteriolar walls (Brown et al. 2000).
A contribution from epoxygenase products to the early phase of the response cannot be discounted, however. EETs are stored in membrane phospholipid pools at the foot processes of astrocytes (Alkayed et al. 1996b; Shivacar et al. 1995; Weintraub et al. 1999) and can be released upon neuronal activation (Zhang et al. 2002). Release of EETs from this store would not be affected by inhibition of the synthesizing enzyme. Thus release of preformed EETs could contribute to the initial phase of activity-evoked dilatation. However, once membrane stores were depleted, the response would not be maintained if the de novo synthesis of EETs was inhibited.
In conclusion, the results of the present study suggest that EETs may be concerned in two aspects of cerebrovascular regulation. Firstly, tonic release of EETs from astrocytes may help to maintain a background level of vasodilator tone within the cerebral vasculature. Secondly, EETs may also play a role, in parallel with other factors such as NO and adenosine, in mediating functional hyperaemia during periods of increased neuronal activity. In vivo, neuronal activity may lead to activation of AMPA receptors on astrocytes by synaptically released glutamate and evoke dilatation of intraparenchymal arterioles and a decrease in the frequency of rhythmic contractile activity (vasomotion). At the onset of the response, the dilatation appears to be independent of epoxygenase activity. Thus any involvement of vasodilator EETs would have to rely on release from membrane stores in astrocytic end-feet in contact with vascular smooth muscle cells. However, during sustained dilatation, de novo synthesis of EETs from arachidonic acid appears to contribute. Astrocyte-derived vasodilator factors may therefore make a significant contribution to the control of nutritive blood flow in the brain and more detailed analysis of their precise role awaits further investigation.
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  V. M. Blanco, J. E. Stern, and J. A. Filosa Tone-dependent vascular responses to astrocyte-derived signals Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2855 - H2863. [Abstract] [Full Text] [PDF]
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 J. A. Filosa, M. T. Nelson, and L. V. Gonzalez Bosc Activity-dependent NFATc3 nuclear accumulation in pericytes from cortical parenchymal microvessels Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1797 - C1805. [Abstract] [Full Text] [PDF]
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 P. G. Haydon and G. Carmignoto Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev, July 1, 2006; 86(3): 1009 - 1031. [Abstract] [Full Text] [PDF]
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significantly different from cannulated vessel, both at P < 0.05; n = 6.
, effect of AMPA in the presence of miconazole. Indicated values for U46619