Kristina Shkirkova, BSc

Liu H, Schwarting J, Terpolilli NA, Nehrkorn K, Plesnila N. Scavenging Free Iron Reduces Arteriolar Microvasospasms After Experimental Subarachnoid Hemorrhage. Stroke. 2021;52:4033–4042.

This study investigated the role of Ferric ions (Fe3+) in the mechanism of microvasospasms secondary to subarachnoid hemorrhage (SAH). Unlike a rapid spike and decrease in intracranial pressure immediately after subarachnoid hematoma, prolonged reduction in cerebral blood flow due to microvasospasms produces a global state of cerebral ischemia that lasts beyond the acute phase of SAH. The acute nature of SAH hematoma damage coupled with prolonged and often delayed states of vasospasm contributes to tissue ischemia and subsequent posthemorrhagic brain damage in SAH.

Previous studies have implicated the role of nitric oxide (NO) in the regulation of cerebral blood flow in the brain and observed a significant decrease in NO levels after SAH. A reduction in microvasospasms was observed when exogenous NO was supplied after SAH.

Given this background, the authors of this study hypothesized that the process of NO depletion is mediated by direct presence of blood supplied iron molecules in the perivascular space, resulting in the formation of reactive oxygen species and subsequent reduction of NO. Mice were exposed to a free iron scavenging agent, iron chelator deferoxamine, prior to inducing SAH via endovascular perforation of the circle of Willis. Visualization of microvasospasms 3 hours after induced SAH in mice with Fe3+ scavenging agent vs controls was performed using a 2-photon microscopy that allows to observe blood flow in animals in-vivo. Results showed that in pial arterioles of animals treated with a scavenger agent, a specific pearl-string-like phenotype was observed; no such pattern was observed in control animals. The authors noted that when all types of vessels were examined, only areas directly covered in hematoma blood showed reduced microvasospasms with Fe3+ scavenger agent. Most commonly, these were observed to be arterioles but not capillaries. Although Fe3+ scavenger agent reduced occurrence of microvasospasms, no effect was observed on the overall parenchymal perfusion, including blood flow velocity of parenchymal vessels and the perfused vessel volume. The authors stated that tissue perfusion is mainly supported by cerebral microcirculation, which relies heavily on capillaries rather than distal arterioles. This may suggest that microvasospasms in capillaries may be affected by different mechanisms than in larger arterioles.

Fe3+ scavenger agent, deferoxamine, used in this study has been previously clinically used to treat iron overload. It important to note that mice exposed to deferoxamine in this study exhibited common side-effects of hypotension and tachycardia compared to control mice, which may, to a certain extent, have an independent effect on the cerebral blood flow.

Overall, this study supports the role of ferric ions in formation of microvasospasms in arterioles but not capillaries in SAH. Reduction in vasospasms, particularly at the level of microcirculation, is an important therapeutic target in SAH.