gms | German Medical Science

Objective: Recently, we characterized cerebral arteriogenesis in a mouse model of chronic cerebral ischemia. However, proximal vessel occlusion in cerebral hemodynamic compromise is usually caused by atherosclerotic cerebrovascular disease. Here, Apolipoprotein E (ApoE) serves as a main cholesterol carrier and ApoE deficiency is associated with increased blood cholesterol levels, inflammation and the subsequent development of atherosclerosis. In the present study, we therefore used a constitutive ApoE knockout mouse to simulate the comorbidity of high cholesterol and atherosclerosis and investigated cerebral collateral vessel growth in a refined model of chronic cerebral hypoperfusion.

Methods: Chronic cerebral ischemia was simulated by unilateral internal carotid artery occlusion (ICAO) or Sham surgery in male, ApoE knockout (ApoE-/-) and wildtype (WT) mice aged 12 weeks. Over 21 days, cerebral resting perfusion and cerebrovascular reserve capacity (CVRC) were quantified by non-invasive Laser Speckle Imaging. On day 21, animals underwent latex/carbon black perfusion for assessment of the basal and leptomeningeal collateral vasculature. In a separate group, brains were harvested for immunofluorescence analysis.

Results: Immediately following ICAO on day 0, resting perfusion and CVRC was significantly reduced in both groups (Resting Perfusion: ApoE-/- 69±7%, WT 67±7% // CVRC: ApoE-/- 8±7%, WT 14±5%; *p<0.05 vs. Sham) but recovered completely until day 21 also in ApoE-/- mice, where collateral outgrowth was surprisingly greater than in WT, which showed diameter increases only in the anterior cerebral artery (*p<0.05 for ApoE-/- and WT vs. Sham) but not in the middle cerebral and internal carotid arteries like ApoE-/- mice (*p<0.05 for ApoE-/- vs. Sham). Moreover, only ICAO in ApoE-/- resulted in a greater overall diameter of leptomeningeal anastomosis (ApoE-/- 23±6µm; *p<0.01 vs. Sham and vs. WT ICAO), which was paralleled by an increased Iba1 signal activity in the cortical region of the affected hemisphere.

Conclusion: An inflammatory response with increased activation and recruitment of Iba1 positive cells may be responsible for the augmented remodeling of the native cerebral collateral vasculature following chronic cerebral ischemia in ApoE deficiency with dyslipidemia and atherosclerosis.