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Abstract
Collateral-dependent blood flow is capable of significantly lessening the severity of stroke. Unfortunately, collateral flow varies widely in patients for reasons that remain unclear. Studies in mice have shown that the number and diameter of cerebral collaterals vary widely due primarily to polymorphisms in genes, e.g., Rabep2, involved in their formation during development. However, understanding how variation in collateral abundance affects stroke progression has been hampered by lack of a method to reversibly ligate the distal middle cerebral artery (MCAO) in mice. Here we present a method and examine infarct volume 24 h after transient (tMCAO, 90 min) versus permanent occlusion (pMCAO) in mice with good versus poor collaterals. Wildtype C57BL/6 mice (have abundant collaterals) sustained small infarctions following tMCAO that increased 2.1-fold after pMCAO, reflecting significant penumbra present at 90 min. Mutant C57BL/6 mice lacking Rabep2 (have reduced collaterals) sustained a 4-fold increase in infarct volume over WT following tMCAO and a smaller additional increase (0.4-fold) after pMCAO, reflecting reduced penumbra. Wildtype BALB/cBy (have a deficient Rabep2 variant and poor collaterals) had large infarctions following tMCAO that increased less (0.6-fold) than the above wildtype C57BL/6 mice following pMCAO. Mutant BALB/cBy mice (have deficient Rabep2 replaced with the C57BL/6 variant thus increased collaterals) sustained smaller infarctions after tMCAO. However, unlike C57BL/6 versus Rabep2 mice, penumbra was not increased since infarct volume increased only 0.3-fold following pMCAO. These findings present a murine model of tMCAO and demonstrate that neuroprotective mechanisms, in addition to collaterals, also vary with genetic background and affect the evolution of stroke.
Highlights
Reversible occlusion of the middle cerebral artery (MCA) in mice is commonly used to model thrombo-embolic stroke in humans in which the obstruction reverses spontaneously or following treatment with a thrombolytic drug or removal by thrombectomy
Despite their more abundant collaterals—and unlike what was seen comparing WT-B6 versus Rabep2−/− mice—infarct volume following permanent MCA occlusion (pMCAO) was only 26% greater than that seen after Transient MCAO (tMCAO) (Figure 2)
To test the hypotheses that mice with more abundant collaterals have larger penumbra and smaller infarct volumes following tMCAO compared to pMCAO, and that tMCAO results in larger penumbra and smaller infarct volumes compared to pMCAO for a given collateral extent
Summary
Reversible occlusion of the middle cerebral artery (MCA) in mice is commonly used to model thrombo-embolic stroke in humans in which the obstruction reverses spontaneously or following treatment with a thrombolytic drug or removal by thrombectomy. While the method has the advantages of ease of performance and not requiring craniotomy, it has several disadvantages that can be difficult to detect and mitigate These include risk of incomplete occlusion and variable interference in flow caused by the filament itself and its promotion of thrombus formation. Other methods have been developed that differ from the filament method and allow use of a thrombolytic drug to simulate the clinical situation, e.g., local intravascular thrombin injection via burr-hole craniotomy or insertion of an exogenously generated thrombus via carotid catheter [1,2,3,4,5,6,7,8,9,10,11] These methods are more difficult to perform and spontaneous thrombolysis can occur, as can variation in drug-induced thrombolysis, infarct size, and appearance of multifocal lesions. While all of the above occur in patients, experimental designs in animal studies generally benefit from approaches that minimize variation in an endpoint(s) for a given level of treatment
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