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

Abstract

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 (nϭ8 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 (47Ϯ16%) and day 28 (46Ϯ7%) groups compared with day 0 (28Ϯ8%), day 1 (33Ϯ19%), day 4 (29Ϯ16%), and sham groups (32Ϯ9%). 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 Ⅲ chronic perfusion Ⅲ collateral circulation Ⅲ focal ischemia Ⅲ ischemic tolerance C ollateral 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 al 3 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 angiography 4 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 siz...

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