Endothelial nitric oxide synthase mediates the cerebrovascular effects of erythropoietin in traumatic brain injury

Abstract

Background: Erythropoietin (Epo) improves post-traumatic cerebral blood flow (CBF), pressure autoregulation, and vascular reactivity to l-arginine. This study examines the dependence of these cerebral hemodynamic effects of Epo on nitric oxide generated by endothelial nitric oxide synthase (eNOS).

Methods: Using laser Doppler flow imaging, CBF was monitored in wild-type (WT) and eNOS-deficient mice undergoing controlled cortical impact followed by administration of Epo (5000 U/kg) or normal saline.

Results: Cerebral blood flow decreased in all groups post-injury with the greatest reductions occurring at the impact site. Epo administration resulted in significantly higher CBF in the peri-contusional sites in the WT mice [70.2 ± 3.35% in Epo-treated compared to 53 ± 3.3% of baseline in saline-treated mice (p < 0.0001)], but no effect was seen in the eNOS-deficient mice. No CBF differences were found at the core impact site where CBF dropped to 20-25% of baseline in all groups.

Conclusion: These differences between eNOS-deficient and WT mice indicate that the Epo mediated improvement in CBF in traumatic brain injury is eNOS dependent.

Keywords: cerebral blood flow; erythropoietin; neuroprotection; nitric oxide; nitric oxide synthase; traumatic brain injury.

Figure 1

Hemodynamic response to the controlled cortical impact (first arrow) followed by administration of the assigned treatment (second arrow). (A) Mean arterial pressure (MAP) changes during the experiment. The animals that were deficient in eNOS had a higher pre-injury MAP and had a greater drop in MAP after injury than the wild-type animals. When the group × time interaction was significant, symbols indicate which treatments were significantly different among the treatments’ groups by the Holm-Sidak post hoc test. (B–D) Cerebral blood flow response measured by laser Doppler in the core (B), contra-lateral (C) and peri-contusional (D) cerebral cortex. The core had a severe persistent drop in CBF regardless of the animal genotype or treatment group. The contra-lateral cortex showed a small to no decline followed by increased perfusion in all groups. In the peri-contusional regions, Epo treatment effect was seen in the WT animals but not in the eNOS-deficient animals (N = 14 per group).