Submitted December 4, 2007
Accepted April 15, 2008
Vascular dysfunction in a murine model of severe hemolysis
Anne C. Frei, YiHe Guo, Deron W. Jones, Kirkwood A. Pritchard Jr., Karen A. Fagan, Neil Hogg, and Nancy J Wandersee*
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, United States
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, United States
Department of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, United States
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, United States
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States
* Corresponding author; email: nancy.wandersee{at}bcw.edu.
Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) due to a mutation in the murine erythroid 
-spectrin gene. sph/sph mice have a high incidence of thrombosis and infarction in multiple tissues, suggesting significant vascular dysfunction. In the current study, we provide evidence for both pulmonary and systemic vascular dysfunction in sph/sph mice. We found increased levels of soluble cell adhesion molecules in sph/sph mice, suggesting activation of the vascular endothelium. We hypothesized that plasma hemoglobin released by intravascular hemolysis initiates endothelial injury through nitric oxide (NO) scavenging and oxidative damage. In agreement, electron paramagnetic resonance spectroscopy showed that plasma hemoglobin is much greater in sph/sph mice. Moreover, plasma from sph/sph mice had significantly higher oxidative potential. Finally, xanthine oxidase, a potent superoxide generator, is decreased in subpopulations of liver hepatocytes and increased on liver endothelium in sph/sph mice. These results indicate that vasoregulation is abnormal, and NO-based vasoregulatory mechanisms particularly impaired, in sph/sph mice. Together, these data indicate that sph/sph mice with severe HS have increased plasma hemoglobin and NO scavenging capacity, likely contributing to aberrant vasoregulation and initiating oxidative damage.
