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(Stroke. 2005;36:2270.)
© 2005 American Heart Association, Inc.

Original Contributions

Chronic Mild Reduction of Cerebral Perfusion Pressure Induces Ischemic Tolerance in Focal Cerebral Ischemia

Kazuo Kitagawa, MD, PhD; Yoshiki Yagita, MD, PhD; Tsutomu Sasaki, MD, PhD; Shiro Sugiura, MD; Emi Omura-Matsuoka, MD; Takuma Mabuchi, MD, PhD; Kohji Matsushita, MD, PhD Masatsugu Hori, MD, PhD

From the Division of Strokology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Correspondence to Kazuo Kitagawa, MD, PhD, Division of Strokology, Department of Cardiovascular Medicine (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail kitagawa{at}medone.med.osaka-u.ac.jp

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Background and Purpose— Neurons acquire tolerance to ischemic stress when preconditioning ischemia occurs a few days beforehand. We focused on collateral development after mild reduction of perfusion pressure to find an endogenous response of the vascular system that contributes to development of ischemic tolerance.

Methods— After attachment of a probe, the left common carotid artery (CCA) of C57BL/6 mice was occluded. The left middle cerebral artery (MCA) was subsequently occluded permanently on days 0, 1, 4, 14, and 28 (n=8 each). The change in cortical perfusion during MCA occlusion was recorded. A sham group of mice received only exposure of the CCA and MCA occlusion 14 days later. In apoE-knockout mice, the MCA was occluded 14 days after CCA occlusion or sham surgery. Infarct size and neurologic deficit were determined 4 days after MCA occlusion.

Results— Mice that had 45% to 65% of baseline perfusion after CCA occlusion were used. Cortical perfusion after MCA occlusion was significantly preserved in day 14 (47±16%) and day 28 (46±7%) groups compared with day 0 (28±8%), day 1 (33±19%), day 4 (29±16%), and sham groups (32±9%). Infarct size and neurologic deficits were also attenuated in day 14 and day 28 groups compared with other groups. In apoE-knockout mice, there was no significant difference in perfusion, neurologic deficits, or infarction size between groups with and without CCA occlusion.

Conclusion— Chronic mild reduction of perfusion pressure resulted in preservation of cortical perfusion and attenuation of infarct size after MCA occlusion. These responses of collaterals were impaired in apoE-knockout mice.

Key Words: chronic ischemia • chronic perfusion • collateral circulation • focal ischemia • ischemic tolerance

	Introduction

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Collateral circulation through leptomeningeal vessels may determine the severity of ischemic injury after occlusion of middle cerebral artery (MCA) in patients with stroke.¹ Although chronic hypoperfusion is believed to be critical for collateral development,² factors leading to it are uncertain. For better understanding of collateral circulation in cerebral ischemia, an animal model in which cerebral collaterals can be investigated is needed. Recently, Busch et al³ demonstrated that 3-vessel (one carotid plus both vertebral arteries) occlusion induced arteriogenesis at the circle of Willis in hypoperfused rat brain. They found that the diameter of the posterior cerebral artery enlarged significantly 1 week after 3-vessel occlusion,³ but the distal leptomeningeal collaterals that determine stroke outcome did not change. Although morphologic assessment of leptomeningeal collaterals requires multivessel angiography⁴ or latex perfusion methods,⁵ the level of collateral circulation after cerebral ischemia can be functionally examined by measuring the change of cerebral perfusion at the time of MCA occlusion. In this study, we examined the effect of a mild reduction of cerebral perfusion pressure by occlusion of the left common carotid artery (CCA) on collateral development and infarct size after MCA occlusion. Furthermore, we examined the effect of apoE deficiency on development of collateral circulation after CCA occlusion because arteriogenesis in knockout mice is impaired in a hindlimb ischemia model.⁶

	Materials and Methods

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C57BL/6 strain mice were obtained from Charles River (Yokohama, Kanagawa, Japan). apoE-knockout mice, originally produced by Zhang et al,⁷ were purchased from the Jackson Laboratory (Bar Harbor, Maine). All mice used in this study were mature males aged 12 to 16 weeks. Mice were given free access to food and water before surgery. The experimental procedures involving laboratory animals have been approved by the Institutional Animal Care and Use Committee of the Osaka University Graduate School of Medicine.

Surgery
General anesthesia was induced with 4.0% halothane and maintained with 0.5% halothane with an open facemask. A polyacrylamide column with an inner diameter of 0.8 mm for measurement of cortical microperfusion by laser-Doppler flowmetry (Advance laser Flowmetry, model ALF-21; Advance Co) was attached with dental cement to the intact skull 3.5mm lateral to the bregma. Laser Doppler flowmetry is not quantitative, but provides a reliable estimate of relative cerebral blood flow. The residual zero flow signal at the time of killing was <2% of baseline perfusion level in a preliminary experiment (n=10). Therefore, we did not determine it in each mouse in the following experiments. Body temperature was monitored with a rectal thermometer and maintained at 37.0°C with a heat lamp.

Common Carotid Artery Occlusion
In the first experiment, in each of 50 C57BL/6 mice, the CCA was ligated and the change in cortical perfusion after CCA occlusion was recorded. Seven days later, mice were killed with an overdose of pentobarbital. The brains were removed, fixed by immersion in an alcohol-5% acetic acid solution for 5 hours at 4°C, dehydrated, and embedded in paraffin. Tissue sections (5 µm) were obtained every 1mm, beginning at the frontal pole, and were examined after conventional staining with hematoxylin and eosin (H&E). In the sections including the hippocampus, the terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) procedure was performed using the Apoptag in situ Detection Kit (Chemicon). In another 8 mice that had 45% to 65% of baseline perfusion after CCA occlusion, the cortical perfusion recordings were measured at 2 hours and 1, 4, 14, and 28 days after CCA occlusion. The change of cortical perfusion after sham surgery was also recorded in the other 8 mice. The level of cortical perfusion was expressed as a percentage of the baseline value.

Middle Cerebral Artery Occlusion Subsequent to Common Carotid Artery Occlusion
In the second experiment, the CCA was ligated under halothane anesthesia. In mice that had 45% to 65% of baseline cortical perfusion after CCA occlusion, the MCA was occluded using electrocoagulation as described previously⁸ on days 0, 1, 4, 14, and 28 (n=8 each). Sham-group mice (n=8) received only exposure of CCA and MCA occlusion 14 days later. Mice were placed in the recumbent position, and a vertical skin incision was made at the midpoint between the left orbit and the external auditory canal. The mandible was pulled downward to expose the skull base. A small burr hole was made in the skull over the left MCA. The MCA was permanently occluded with a microbipolar electrocoagulator just proximal to the point where the olfactory branch came off. Cortical perfusion was monitored under halothane anesthesia for 15 minutes after MCA occlusion. Four days after MCA occlusion, mice were evaluated for neurologic deficits by a blind observer. The neurologic deficit score assignment of 0 to 4 was based on methods described previously by Yang et al⁹: 0, no neurologic deficits; 1, failed to extend right forepaw while held by the tail; 2, circled to the right; 3, fell to the right; or 4, unable to walk spontaneously. Then, mice were killed under pentobarbital anesthesia, and their brains were removed, fixed, and embedded in paraffin. The volume of infarction was measured using MCID Image Analysis Software (Imaging Research). The volume (mm³) was determined by integrating the appropriate area and the section thickness. To visualize the capillary perfusion, we labeled plasma with dichrolotriazinyl amino fluorescein (DTAF; excitation 489 nm, emission 515 nm; Sigma-Aldrich) as described previously.⁸ After MCA occlusion for 6 hours in mice with CCA occlusion or sham operation 14 days earlier, 50 µL of DTAF conjugated to mouse serum was injected for 10 seconds into the saphenous vein. Thirty seconds after completion of the injection, each mouse was decapitated and the brains were fixed in 80% ethanol for 24 hours. Brain slices, 50 µm in thickness, were prepared with a vibratome and examined under a fluorescence microscope. In mice with CCA occlusion or sham operation 14 days earlier (n=5 each), a femoral artery was cannulated with a PE-10 polyethylene tube at the time of MCA occlusion. Blood pH, PaO₂, and PaCO₂ were measured using the Acid-Base Laboratory system (ABL550; Radiometer).

Effect of Common Carotid Artery Occlusion in apoE-Knockout Mice
In the last experiment, we used apoE-knockout mice. The left CCA of apoE-knockout mice (n=8) was ligated under halothane anesthesia. Fourteen days later, the left MCA was permanently occluded. Sham-group mice (n=8) received only exposure of the left CCA and occlusion of the left MCA 14 days later. Four days after MCA occlusion, mice were evaluated for neurologic deficits, and they were killed and their brains were examined for infarction size. The experiment schedule is shown in Figure 1.

View larger version (22K): [in this window] [in a new window]   Figure 1. Experimental schedule. (A) The left CCA in 50 C57BL/6 mice was occluded and their brains were examined 7 days later. In another 16 mice, the cortical perfusion recordings were monitored until 28 days after CCA occlusion (n=8) or sham operation (n=8). (B) The left CCA was ligated first, and the left MCA was subsequently occluded on days 0, 1, 4, 14, and 28 (n=8 each). Neurologic deficit and infarct size were evaluated 4 days after MCA occlusion. (C) In apoE-knockout mice, the left MCA was permanently occluded 14 days after CCA ligation (n=8) or sham operation (n=8). CCAO indicates common carotid artery occlusion; MCAO, middle cerebral artery occlusion.

Statistics
All values are presented as mean±standard deviation. One-way analysis of variance (ANOVA) was performed with Scheffe’s multiple comparisons test to assess differences in perfusion change, neurologic deficit, score and infarct size between day 0, day 1, day 4, day 14, day 28, and sham groups. The perfusion values after CCA occlusion were analyzed by repeated-measures ANOVA followed by a post hoc Dunnett test. A Mann–Whitney U test was performed to assess differences between 2 groups of apoE-knockout mice. Pearson’s test was used to evaluate the relationship between perfusion change after CCA occlusion and that after MCA occlusion. P<0.05 was considered significant. All statistical analyses were conducted using SPSS/Windows software, version 11.5J (SPSS Japan Inc).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Unilateral occlusion of the left CCA resulted in 40% to 70% of baseline microperfusion over the MCA area in most mice. However, in 6 mice, cortical microperfusion was reduced to less than 35% of baseline (Figure 2). On the basis of histologic examination, one mouse showed infarction in the cortex, caudoputamen, and hippocampus, and 2 mice showed ischemic neuronal damage in the hippocampus with fragmented DNA detected by the TUNEL method (Figure 2B). In the other 47 mice, no ischemic damage was found (Figure 2B). Because more than 70% of mice had 45% to 65% of baseline cortical perfusion, we used those mice in the subsequent experiment. In the control group, the mean cortical perfusion after the sham operation varied from 90% to 111% without any significant changes between any time intervals. The cortical perfusion values decreased to 59.0±4.6%, 59.3±6.9%, and 55.4±9.0% at 2 hour and 1 and 4 days, respectively, and remained significantly lower at 14 (61.4±11.6%) and 28 days (63.2±14.0%) after CCA occlusion as compared with the baseline value (Figure 2C).

View larger version (31K): [in this window] [in a new window]   Figure 2. (A) Cortical perfusion as percent of baseline and histologic damage after CCA occlusion. Results from 50 C57BL/6 mice are plotted based on the change in perfusion and histologic damage. Three of 6 mice that showed less than 35% of baseline perfusion had ischemic neuronal damage or infarction in the ipsilateral hemisphere. Mice were used in subsequent experiments, which showed 45% to 65% of baseline perfusion after CCA occlusion (range indicated with dotted lines). (B) (a) TUNEL staining in the hippocampal CA1 sector of a mouse showing 30% of baseline perfusion after CCA occlusion. Numerous neurons with positive reaction were observed. (b) In the hippocampus of a mouse showing 55% of baseline perfusion, there was no TUNEL-positive neuron. (C) Cortical perfusion values after CCA occlusion (solid lines) and sham operation (dotted lines). *P<0.01 compared with the sham operation.

The change in the cortical perfusion after MCA occlusion compared with that before CCA operation, the perfusion change at the time of MCA occlusion, neurologic deficit score, and infarct size 4 days after MCA occlusion are shown for each group in Figure 3. CCA occlusion and subsequent MCA occlusion reduced perfusion to 15% to 20% in day 0, day 1, and day 4 groups (Figure 3A). However, in day 14 and day 28 groups, the change in perfusion after CCA and MCA occlusion were approximately 30% and were significantly higher than those of day 0, day 1, and day 4 groups (Figure 3A). In the sham-operation group, the change in perfusion after sham CCA operation and MCA occlusion was 31.8±9.0%, higher than those in day 0, day 1, and day 4 groups but not significant different compared with those in day 14 and day 28 groups (Figure 3A). At the time of MCA occlusion, cortical perfusion reduced to approximately 30% of baseline in day 0, day 1, day 4, and sham CCA exposure groups (Figure 3B). However, in day 14 and day 28 groups, the changes in perfusion at the time of MCA occlusion were 47.6±15.8% and 46.1±6.7%, respectively, and were significantly preserved compared with other groups (Figure 3B). In day 14 and day 28 groups (n=16), there was significantly negative correlation between the perfusion change after CCA occlusion and that at the time of MCA occlusion (r=–0.686, P<0.01). Both neurologic deficit score (Figure 3C) and infarction size (Figures 3D and 4) were significantly attenuated in day 14 and day 28 groups compared with other groups. Reduction of infarction size was markedly observed in the cerebral cortex (Figures 3D and 4). Capillary fluorescence was hardly observed in the center of the MCA territory in sham operation group (Figure 4). In contrast, capillary perfusion in the same territory was better preserved in day 14 group (Figure 4). The physiological variables were determined for mean arterial blood pressure (day 14 group, 76.6±4.3 mm Hg; sham operation group, 77.0±3.4 mm Hg), PaCO₂ (day 14 group, 35.2±3.3 mm Hg; sham operation group, 34.4±2.8 mm Hg), PaO₂ (day 14 group, 119.6±9.2 mm Hg; sham operation group, 120.2±8.8 mm Hg), and pH (day 14 group, 7.29±0.07; sham operation group, 7.32±0.04 mm Hg). There were no significant differences in any of the variables between day 14 and sham-operation groups.

View larger version (60K): [in this window] [in a new window]   Figure 3. Effect of CCA occlusion and sham CCA operation (A) on the cortical perfusion after MCA occlusion compared with that before CCA operation, (B) on the cortical perfusion at the time of MCA occlusion compared with that before MCA occlusion (C) on the neurologic deficit score, and (D) on the infarct size. In (D), infarct size of the subcortical area in each group was shown as black parts of the columns. Day 0 indicates MCA occlusion on the same day as CCA occlusion. MCA was occluded on days 0, 1, 4, 14, and 28 after CCA occlusion. Sham group mice received only exposure of CCA 14 days before MCA occlusion. * P<0.05 compared with day 0, day 1, and day 4 groups. #P<0.05 compared with day 0, day 1, day 4, and sham groups. In day 14 and day 28 groups, cortical perfusion after MCA occlusion is preserved, neurologic scores are less severe, and infarct size is attenuated.

View larger version (72K): [in this window] [in a new window]   Figure 4. Capillary perfusion in the cerebral cortex and hematoxylin and eosin staining in the whole brain after MCA occlusion. In the mouse that received a sham CCA operation 14 days before MCA occlusion (SHAM-14D-MCAO), severe reduction of perfused microvessels and infarction was seen in the entire MCA territory. A preserved microcirculation and smaller infarct area was seen when CCA was occluded 14 days before MCA occlusion (CCAO-14D-MCAO).

In apoE-knockout mice, the change in cortical perfusion, the neurologic score, and infarct size are shown in Figure 5. In apoE-knockout mice, the CCA occlusion treatment group (n=8) and the sham CCA exposure group (n=8) showed no significant difference in cortical microperfusion after CCA occlusion and subsequent MCA occlusion (29.5±9.0% compared with 30.4±8.5%), perfusion change at the time of MCA occlusion (36.4±11.8% compared with 30.2±7.8%), in neurologic scores (1.5±0.8 compared with 1.9±1.0), or in infarct size (31.5±8.2 mm³ compared with 37.0±5.3 mm³, P=0.14).

View larger version (39K): [in this window] [in a new window]   Figure 5. Diminished effect of CCA occlusion treatment in apoE-knockout mice. apoE-knockout mice received CCA occlusion or sham surgery; 14 days later, they received MCA occlusion. There is no significant difference in the (A) cortical perfusion after CCA and MCA occlusion, (B) cortical perfusion at the time of MCA occlusion, (C) neurologic deficit score, and (D) infarct size.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Leptomeningeal collaterals that may maintain perfusion beyond the site of an arterial occlusion have been appreciated as an important factor both in modifying the size of infarction and in clinical outcome after embolic occlusion of the MCA.^1,10 Angiogenesis after MCA occlusion has been intensively investigated.^11,12 However, little is known about the factors that determine collateral development at the time of embolic occlusion. MCA occlusion has been shown to induce growth and enlargement of surface collaterals in the ischemic border.¹³ Chronic hypoperfusion resulting from extracranial and intracranial occlusive disease promotes leptomeningeal collateral formation, although collaterals require time to develop.^5,10,13 The precise role of chronic hypoperfusion in collateral development remains unclear, although it is known that the efficacy of collateral vessels also depends on age, hypertension, and associated comorbidities.¹⁴

Recently, arteriogenesis at the circle of Willis has been demonstrated clearly in a 3-vessel (1 carotid plus both vertebral arteries) occlusion model.³ Although reduction of perfusion pressure promotes arteriogenesis at the circle of Willis and in the distal anastomoses that have been described as "pre-existing collateral arterioles,"¹⁵ the diameters of leptomeningeal anastomoses in the 3-vessel occlusion model did not change.³ The estimation of vessel diameters may be insufficient for assessing collateral development, particularly in the ischemic condition. Resting cortical perfusion level remained 60% of baseline up to day 28 after CCA occlusion (Figure 2C), suggesting us to use a functional evaluation of collateral circulation by measuring the cortical perfusion at the time of MCA occlusion. We first examined the effect of unilateral CCA occlusion on cortical perfusion and histologic damage. Very few mice (6 of 50) showed moderate to severe ischemia (<35% of baseline) after unilateral CCA occlusion, and only 3 of them had histologic damage in the affected hemisphere. Therefore, in the present study, we used mice that showed 45% to 65% of baseline cortical perfusion.

Our results demonstrated that unilateral CCA occlusion treatment given 14 days before MCA occlusion preserved cortical perfusion and reduced infarct size markedly in the cerebral cortex after MCA occlusion. Negative correlation between changes in perfusion after the first CCA occlusion and at the time of subsequent MCA occlusion in day 14 and day 28 groups suggests that sufficient reduction of perfusion pressure is needed for collateral development. The time required to develop the effects in the present study is in agreement with the findings about collateral vessel development in hindlimb ischemia models.¹⁶ In general, the development of preexisting collateral arterioles into large conductance vessels may take days to weeks after a critical stenosis of the proximal artery.¹⁵ A direct neuroprotective preconditioning effect after chronic ischemia as shown in the previous study¹⁷ may in part contribute to the effect in day 14 and day 28 groups. Furthermore, coagulation status such as platelet accumulation and fibrin deposition may change after chronic ischemia as suggested in hypoxia-tolerant states.¹⁸

Because several studies demonstrated that disordered lipid metabolism may impair collateral vessel growth and angiogenesis in other organs,⁶ we examined the effect of unilateral CCA occlusion in apoE-knockout mice. We found that collateral development was impaired in apoE-knockout mice, suggesting that common mechanisms underlie arteriogenesis in the brain and systemic circulation. Based on the previous findings, possible mechanisms of collateral development after chronic hypoperfusion would be (1) fluid shear stress leading to endothelial activation, (2) monocyte invasion, and (3) proliferation of smooth muscle cells and vessel enlargement.¹⁹ Involvement of growth factors or cytokines such as VEGF⁶ and granulocyte-macrophage colony-stimulating factor²⁰ in collateral development in the brain will need to be investigated further.

Endogenous adaptive responses to ischemic insults such as ischemic tolerance²¹ have received much attention, and it is widely believed that this phenomenon is largely the result of an endogenous response such as gene expression in the preconditioned neuron.^22,23 However, vessel components should also be targets for investigation of endogenous response. Thus, we have clarified that chronic mild reduction of perfusion pressure leads to collateral development and brain protection after focal cerebral ischemia.

	Acknowledgments

 
The authors thank Ms. A. Kanzawa and S. Higa for secretarial assistance. This work was supported by a Grant-in-Aid from the Ministry of Education, Science, and Culture in Japan.

Received January 18, 2005; revision received June 22, 2005; accepted July 6, 2005.

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