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CARDIOVASCULAR |
1 Biological Services Unit and Department of Physiology, University College Cork, Ireland
2 Cardiovascular Medicine, Department of Medicine and Therapeutics, University of Aberdeen, UK
3 School of Pharmacy, Robert Gordon University, Aberdeen, UK
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Abstract |
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(Received 31 January 2006;
accepted after revision 9 March 2006;
first published online 16 March 2006)
Corresponding author R. Kelly: Biological Services Unit, University College Cork, Cork, Ireland. Email: rokelly81{at}gmail.com
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Introduction |
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If the latter, it is necessary to consider that all blood vessel linings are coated with the vascular endothelial glycocalyx, a highly negatively charged structure, rich in anionic sites mostly represented by the sialic acid moieties of glycoproteins and the sulphate and carboxyl groups of heparan sulphate proteoglycans, about 0.5 µm thick (Vink & Duling, 1996). The glycocalyx has been implicated as a protective factor against leucocyte adhesion to endothelial cells (Mullivor & Lipowsky, 2002) and myocardial oedema (Van den Berg et al. 2003) and as the sensor for vessel dilatation resulting from shear stress on the endothelial surface (Snow et al. 2001; proteoglycans interact via their transmembrane core protein with the cell cytoskeleton, see Weinbaum et al. 2003), i.e. the glycocalyx senses increased shear rate (Weinbaum et al. 2003) and signals the endothelial cell to release nitric oxide (Joannides et al. 1995). Impairment of flow-dependent dilatation has been shown in rabbit femoral and mesenteric arteries by neuroaminidase degradation of the sialic acid residues of endothelial glycocalyx (Hecker et al. 1993). In addition, nitric oxide production by cultured endothelial cells in response to fluid shear stress is inhibited after enzymatic removal of heparan sulphate proteoglycans (Florian et al. 2003).
In this study, the importance of the glycocalyx in mechanotransduction was studied in the intact animal by: (a) investigation of the pure shear-stress response, differentiated from the acetylcholine response; and (b) investigation of whether glucose produces a differential block of the former. The reasoning for (b) was that glucose interacts with the proteoglycans (Rosenberg et al. 1997) and glycosaminoglycans (Arisaka et al. 1995) of the glycocalyx, and this may take place under hyperglycaemic conditions. There is already evidence that glucose affects glycocalyx volume (Zuurbier et al. 2005). Unfortunately, systemic hyperglycaemia involves insulin release, and insulin has complex haemodynamic effects (Baron, 1994). Therefore, the eventual experimental approach undertaken in this study was the exploration of luminal hyperglycaemia.
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Methods |
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Experimental procedures
End-tidal partial pressure of CO2 was maintained between 34 and 40 mmHg by positive pressure ventilation using a Palmer pump via a tracheotomy; hypoxia was prevented by adding 40% oxygen to the inspired air. The left iliac artery was dissected from the aortic bifurcation to the deep femoral branch. A catheter-tip manometer, sometimes with lumen for infusion of acetylcholine (upstream cannula) was inserted via the right iliac artery or the mesenteric artery into the base of the aorta. The distal (test) segment was cannulated via the deep femoral artery. The right iliac artery, sacral artery, and all branches of the left iliac and mesenteric arteries were ligated. The details of the preparation are illustrated in Fig. 1.
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Experimental protocol 1 (n = 7). Through the upstream cannula, a 50% glucose solution (as used clinically for the treatment of hypoglycaemia) was infused at a rate calculated to achieve an approximate concentration of 40 mM in the blood flowing down the iliac artery and the effects of shear stress and ACh were observed before and after the infusion.
Experimental protocol 2 (n = 11). In nine animals, a protocol was followed in which blood was withdrawn into a heparinised syringe from the animal and its glucose concentration was raised from normal (measured as 5.7 ± 0.9 mM, mean ± S.D., n = 9) to high (at least 20 mM). These samples were introduced into the distal arterial segment by closing both snares, stopping blood flow through the iliac artery, and irrigating the isolated distal segment for 20 min through the distal cannula (see Fig. 1); the fluid being changed every 2–3 min. In two animals, high glucose in saline (0.9%) was used.
We have previously established that snaring without irrigation had no effect on subsequent flow-dependent arterial dilatation. We started by introducing glucose at 20 mM and, if the effect on vasodilation was not reduced, increased the concentration, rather than the exposure time (the lower limb is ischaemic during the test). The concentration required to obtain a complete response was therefore variable (see Table 2). Each successful response was repeated at least twice in each preparation.
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First, to test that the administration of blood into the test segment did not affect responses, protocol 2 was repeated using normoglycaemic blood. Second, both snares were occluded with no fluids inserted to test that collapse of the artery below its normal diameter did not affect the response.
To ensure that the results were specific to the D-optical isomer of glucose, L-glucose (30 mM) in blood was infused into the test segment.
Two procedures were employed to test the mechanisms postulated to be involved in glucose-induced blockage of the shear stress response. First, hyaluronidase (0.28 µg ml–1) in blood was infused to show that disruption of the glycocalyx leads to attenuation of the shear stress response but preservation of the response to acetylcholine as predicted by the results reported by Mochizuki et al. (2003). Second, in order to exclude the participation of non-NO mediators in the responses (Pyke & Tschakovsky, 2005), L-NAME was administered systemically to reconfirm, in this preparation, that the responses to shear stress and acetylcholine are mediated by nitric oxide.
Calculation of shear stress (Nm–2)
Shear stress was calculated as:
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The response was quantified as microns of increase of mean arterial diameter divided by the increase in mean shear rate.
Measurement of blood glucose
All glucose levels reported in results were measured using a Glucometer (Bayer) by withdrawing a 1 ml sample of blood and placing a drop of it on a Glucotide blood glucose test strip. If the blood glucose level was too high to be read by the glucometer, another 1 ml sample was taken and diluted, and the measurement repeated. The new reading was multiplied by the dilution factor to arrive at the blood glucose value. We started by introducing glucose at 20 mM and, if the effect on vasodilation was not reduced, increased the concentration rather than the exposure time (the lower limb is ischaemic during the test). The concentration required to obtain a complete response was therefore variable.
Statistics
Fisher's exact test, 
2 tests, and Wilcoxon matched-pairs signed-ranks test were carried out using InStat software (Graph Pad, San Diego, CA, USA). A value of 0.05 was regarded as significant.
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Results |
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Protocol 1
Upstream infusion of glucose caused attenuation of the shear stress-dependent response in both segments with preservation of the acetylcholine response (Fig. 2).
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Protocol 2
Exposure of the test segment lumen to glucose abolished or reduced the amplitude of the flow-dependent arterial dilatation in this segment, with preservation in the control segment (Fig. 4A and B); the acetylcholine response was preserved in both segments (Fig. 4) during repeated tests of both stimuli.
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The results in Fig. 4A and B are clear cut, but in the other experiments it may have been possible that a positive result was obtained artifactually. We therefore set criteria that should be met in the protocol (Table 2).
In all experiments, the attenuation of the flow response in d2 was accompanied by its preservation in d1. All experiments were associated with the presence of a static column of blood above the proximal snare, removal of which (after intraluminal glucose exposure), re-exposed d2 to arterial pressure, accompanied by a step up and a slow increase of the diameter of d2 before settling to a new steady value. Three of 11 experiments were unequivocal according to all the criteria in Table 2.
One experiment (no. 8) failed the vital test that diameter during an acetylcholine response should exceed diameter during the shear stress test. Counting this experiment as negative, the probability that the effect of glucose on the test segment occurred by chance was < 0.025 by 2 test with correction for continuity, considered statistically significant.
The quantified results for protocol 2, plotted in a similar manner to Fig. 3, are shown in Fig. 5. The response to shear stress diminished in all 11 experiments. It was also observed (right-hand panel) that there was always an increase in the baseline external diameter (P = 0.001). The responses to acetylcholine before and after glucose in the test segment (accompanied by block of the shear stress response) were measured in nine experiments. The increase in diameter was divided by the shear stress increase and normalized to the control segment response. The results are presented in Fig. 6. The P value was 0.6523 by Wilcoxon matched-pairs signed-ranks test (not significant).
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In the control experiments, occlusion of both snares, with or without insertion of normoglycaemic blood into the test segment, had no effect on the shear stress or acetylcholine responses (Fig. 4A). Likewise, L-glucose had no effect (Fig. 4B). Hyaluronidase caused attenuation of the shear stress response, with preservation of the acetylcholine response (Fig. 7), confirming the results of Mochizuki et al. (2003) by acting on the glycocalyx. L-NAME abolished both shear stress (Fig. 8) and acetylcholine responses, reconfirming, in this preparation, that these responses are mediated by nitric oxide.
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Discussion |
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(TNF-; Henry & Duling, 2000) and oxidized low-denisty lipoproteins (LDL; Vink et al. 2000; Constantinescu et al. 2003) and has also been postulated for vascular disease related to hyperlipidaemia (Vink et al. 2000; Constantinescu, 2002). Moreover, the fact that disturbed shear stress patterns initiate molecular changes leading to lipid accumulation in the arterial wall (Chien, 2003) indicates the primary role of the mechanotransducer in this process. This is also suggested by the finding that relatively high shear stress (protective) may suppress atherogenesis by altering the synthesis of glycosaminoglycans (Arisaka et al. 1995). There is also evidence to suggest that glucose has an inflammatory effect, acting via generation of reactive oxygen species, and that this may be counteracted by an anti-inflammatory effect of insulin (Dandona et al. 2005). Contrary to this, it is claimed that, using euglycaemic clamp, insulin causes endothelium-dependent vasodilatation in large conduit arteries, probably by increasing oxidant stress (Arcaro et al. 2002; Singleton et al. 2003). Thus, oxygen radical production to inhibit glycocalyx function is another possible mechanism of action of glucose (Gross et al. 2003), although the failure to reverse glucose-induced impairment of relaxation in response to acetylcholine (Pieper et al. 1995) suggests otherwise.
Glucose infusion (protocol 1) had many disadvantages, including the fact that it took approximately an hour for shear stress responses to be inhibited; this is similar to the time taken for a change in glycocalyx permeability in mice (Zuurbier et al. 2005). By this time, arterial baseline dilatation had obscured the picture. It then took about 4 h for the blood glucose level to return to normal. Therefore, it was not possible to make repeated measurements within the lifetime of the preparation. Infusion of glucose results in an increase in iliac blood flow (Fig. 2), as in the coronary bed when insulin is held at normal levels with octreotide (Capaldo et al. 2005). Such an increase in flow will cause a baseline dilatation owing to shear stress-induced arterial dilatation. In protocol 1, as depicted by the data in Fig. 2, how does one explain the baseline dilatation when the shear stress response is blocked? In protocol 1, although the simulation of clinical conditions would certainly have caused insulin release, insulin rises within minutes after the start of an intravenous glucose infusion (Toschi et al. 2002). Insulin augments the effect of acetylcholine on peripheral arterioles and, to a lesser extent, that of nitroprusside (Rask-Madsen et al. 2003). Insulin also increases capillary blood volume (Dawson et al. 2002), endothelin-1 levels (Ferri et al. 1995; Cardillo et al. 1999), and serotonin (endothelium–NO)-dependent vasodilatation (Hermann et al. 2004). Remarkably, insulin infused intra-arterially does not increase blood flow (Cardillo et al. 1998, 1999), but only systemic hyperinsulinemia does so (Cardillo et al. 1998), i.e. there is an indirect mechanism by which hyperinsulinaemia causes generalized nitric oxide release (Cardillo et al. 1998). These complicated effects raise the possibility that the attenuation of the shear stress response seen with protocol 1 might not be only an effect of glucose on the glycocalyx. Also, this protocol does involve exposure of all tissue in the arterial wall to hyperglycaemia, not only the luminal surface.
As discussed above, results from protocol 1 are uncertain, so our conclusions have to be based on the results of protocol 2, which involved occlusion of the artery for 20 min. In protocol 2, after glucose, the positive response to acetylcholine was observed (in time) between two blocked shear stress responses. After glucose, the absence of a shear stress response was observed (in time) between two positive acetylcholine responses, i.e. ‘sandwich’ experiments, showing that the blockade of the shear stress response occurs at a time when the endothelial cells are capable of producing nitric oxide. The fact that glucose added to flowing blood (in protocol 1) attenuates the shear stress response in the presence of the acetylcholine response also shows that blockade of the shear stress response is caused by hyperglycaemia, and not by occlusion of the artery.
It is acknowledged that the glucose concentrations used in protocol 2 are higher than the clinical range of patients with glucose intolerance. The use of high blood glucose concentrations for 20 min (Table 2) was prompted by the fact that during the exposure time the hind leg of the animal becomes ischaemic. In pilot experiments, 20 min was found to be the minimum exposure time for blockade of the response. Since, in this protocol, the option of increasing the duration of exposure to 3 h used by Zuurbier et al. (2005) or 6 h used by Williams et al. (1998) was not possible, the concentration of glucose was increased instead. Experimentally, concentrations of 25 mM were used to demonstrate inhibition of the acetylcholine response after 3 h exposure in a rabbit model (Gomes et al. 2004) and in a rat model (Pieper et al. 1995). These concentrations are comparable to the higher levels that are seen in clinical practice (Gomes, 2004). Therefore, another advantage of our short exposure times is that the acetylcholine response would be preserved, enabling us to differentiate the mechanosensor defect from the ability of the endothelial cells to produce nitric oxide.
The data generated in protocol 2 may not reflect a direct action of glucose on the endothelial cells because it takes 5–10 days of direct exposure, not 20 min, to induce impairment of bradykinin-induced nitric oxide release (Tang & Li, 2004). Furthermore, such exposure of an artery ex vivo to glucose (Tang & Li, 2004) will expose all layers, not just the luminal surface, and will lead to inhibition of the acetylcholine response and the generation of free radicals (Yakubu et al. 2004).
A limitation of the present study was the difficulty in reproducing the blockade of the shear stress-dependent dilatation by glucose in all experiments according to the ideal experimental criteria (Tables 1 and 2). Thus it is possible to obtain results in which complete blockade is not evident. However, the overall results with intraluminal glucose (Fig. 5 and Table 2) suggest that the effect of glucose is genuine; the probability of this not being the case is estimated at < 0.05. There is no doubt that differential block of the shear stress response is possible with preservation of the acetylcholine response, demonstrated by the effects of D-glucose (Fig. 4) and hyaluronidase (Mochizuki et al. 2003). It is proposed, therefore, that the endothelial cells themselves do not sense the shear stress, but that this signal is transmitted to the endothelial cells by the glycocalyx.
The lack of effect of L-glucose would seem to exclude the possibility that the effect seen is an osmotic effect rather than one specific to D-glucose. The findings of a clear cut differential block of the shear stress response in protocol 2 (Fig. 4), together with the convincing examples of differential block with the first protocol (Fig. 2) lead us to conclude that D-glucose (probably luminal D-glucose) attenuates or abolishes endothelial mechanotransduction.
Normoglycaemic blood put into the test segment, or occlusion of the snares alone, had no effect on the shear stress response. The mere occlusion of the snares or the presence of stagnant blood is not responsible for the block following hyperglycaemia in this segment. This lack of effect of the snaring technique (which might affect oxygen and metabolite concentrations) on subsequent flow-dependent vasodilatation was demonstrated by the lack of effect of normoglycaemic blood (Fig. 7, left panel) and the lack of effect of L-glucose (Fig. 4B, right panel). Both these interventions involved double snaring.
Shear stress- and acetylcholine-induced arterial dilatation are mediated by nitric oxide release from endothelial cells. According to Hecker et al. (1993), shear stress also causes prostacyclin release. We do not think that prostacyclin is involved in our experiments, however, since shear stress responses were abolished by L-NAME, suggesting that all responses in our experiments are mediated by nitric oxide.
There are two main findings in this study. First, arterial dilatation in response to increased shear stress can be blocked while preserving the response of the endothelial cells to acetylcholine; this indicates that the shear stress signal is mediated by something between the blood and the cell, postulated to be the glycocalyx. Both of these responses are nitric oxide dependent, as shown by the L-NAME experiments. Second, such differential block can be obtained by exposing the lumen alone to higher than normal glucose concentrations. This block is specific to the D-optical isomer of glucose.
It is not clear to us whether the lack of shear stress stimulation of hyaluronan incorporation into the glycocalyx (Gouverneur et al. 2006) would happen if the arterial dilatation induced by shear stress were to be blocked by intraluminal dextrose. The doubt is caused by the fact that the shear stresses are still present and might induce hyaluronan incorporation independently. Dextrose and other atherogenic risk factors appear to cause thinning of the glycocalyx (Van den Berg et al. 2006), but whether this is related to block of shear stress-induced arterial dilatation is also uncertain. It seems to us important that future work should explore the effect or otherwise of other atherogenic risk factors than dextrose upon shear stress-induced arterial dilatation in order to determine whether there is an absolute correlation between positive effect and glycocalyx thinning effects.
Flow-mediated endothelial transduction (Davies, 1995) has been shown to involve extracellular matrix and cell proteins (Davies & Tripathi, 1993; Malek & Izomo, 1994; Girard & Nerem, 1995; Osol, 1995; Hutcheson & Griffith, 1996), such as F-actin, integrin and vimentin. Microtubules may also be involved (Sun et al. 2001). Moreover, it has been shown that mere defunctioning of glycocalyx hyaluronic acid and glycosoaminoglycans can abolish the shear stress dilatory response (Mochizuki et al. 2003). The findings of this study may indicate the following theoretical mode of action: the glycocalyx gel phase determines the mechanical response of the glycocalyx, while the proteinacious ‘hairs’ within the gel, which transmit the signal to the endothelial cellular cytoskeleton, depend for correct strain (in response to change in shear stress) upon the mechanical response of the gel phase. The strain transmitted to the cell cytoskeleton could then trigger the release of calcium ions (Muller et al. 1999), or increase intracellular calcium ion concentration from sodium–calcium exchange (Tang & Li, 2004), leading to activation of endothelial nitric oxide synthase (eNOS) and increased release of nitric oxide. Relaxation of vascular smooth muscle would then seem to be just a response to nitric oxide; mechanotransduction by vascular smooth muscle itself (Osol, 1995) appears to us unlikely.
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