Vascular dysfunction in a murine model of severe hemolysis.
Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) because of a mutation in the murine erythroid alpha-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. Likewise, 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.
Frei
Anne C
AC
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
Guo
YiHe
Y
Jones
Deron W
DW
Pritchard
Kirkwood A
KA
Fagan
Karen A
KA
Hogg
Neil
N
Wandersee
Nancy J
NJ
D000818:Animals; D004195:Disease Models, Animal; D006454:Hemoglobins; D006461:Hemolysis; D006976:Hypertension, Pulmonary; D008099:Liver / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide; D013049:Spectrin / Q000235:genetics*; D013103:Spherocytosis, Hereditary / Q000503:physiopathology*; D014664:Vasodilation; D014969:Xanthine Oxidase
D006454:Hemoglobins; D013049:Spectrin; D009569:Nitric Oxide; D014969:Xanthine Oxidase