Effects of Extracellular Superoxide Dismutase on Arterial Vascular Structural Changes After Acute Subarachnoid Hemorrhage in the Mouse
Background and Purpose: Subarachnoid hemorrhage (SAH) is a known cause of cerebral vasospasm. Vasopasm may result from loss of endothelial NO synthesis. There is also evidence that Hgb products released after SAH bind NO and deplete its extracellular bioavailability. Cu/Zn superoxide dismutase (SOD) overexpression has been shown to provide protection against vasospasm presumably by reducing available superoxide to react with and deplete NO thereby increasing NO concentration. This study characterized the effects of extracellular SOD (EC-SOD) on vasospasm comparing transgenic EC-SOD overexpressing mice to wild type (WT) counterparts. Methods: Mice underwent halothane anesthesia and endovascular perforation of the right proximal anterior cerebral artery (ACA) using a 5–0 monofilament. Sham mice underwent surgery but no vascular perforation. Temperature, blood gases, & blood pressure were maintained within normal ranges. Three days after recovery, brains were sectioned and Gomori’s trichromic stained. Vascular wall thickness was measured in triplicate sections from the proximal and distal segments of the ACA with the observer blinded to genotype. N=5 per group. Results: There was no difference in wall thickness between EC-SOD overexpressors and wild type shams in either ACA segment (Proximal: EC-SOD = 64±22μm, WT = 72±8μm, p=0.62; Distal: EC-SOD = 77±13μm, WT = 68±9μm, p=0.2). For both genotypes, SAH caused increased wall thickness which was greater in the EC-SOD vs. wild type SAH groups in the proximal (EC-SOD = 164±9μm, WT = 108±27μm, p=0.01) but not distal (EC-SOD =136±37μm, WT = 106±38μm, p=0.28) ACA segments. Conclusions: We were unable to demonstrate amelioration of vasospasm by the five-fold increase of brain EC-SOD known to occur in these mutants. In fact, in the proximal ACA, wall thickness was greater in the EC-SOD overexpressors subjected to SAH. Absence of a beneficial EC-SOD effect might be attributable to the post-SAH measurement interval when processes other than NO metabolism are likely to account for vasospasm. The reason for the pattern of an adverse effect of EC-SOD overexpression is unknown.