Health & Environmental Research Online (HERO)


Print Feedback Export to File
3237233 
Journal Article 
Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice 
Kaul, DK; Liu, XD; Chang, HY; Nagel, RL; Fabry, ME 
2004 
Yes 
Journal of Clinical Investigation
ISSN: 0021-9738
EISSN: 1558-8238 
114 
8 
1136-1145 
WOS:000224537700020 
In sickle cell disease, intravascular sickling and
attendant flow abnormalities underlie the chronic inflammation and vascular endothelial
abnormalities. However, the relationship between sickling and vascular tone is not well
understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative
stress will affect microvascular regulatory mechanisms. In the present studies, we have examined
whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice
(which express exclusively human alpha- and beta(s)-globins with <1% gamma-globin levels) are
amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK
mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation,
compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated
vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate
oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e.,
prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated
vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK +
gamma mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced
oxidative stress and hemolytic rate. Furthermore, BERK + gamma mice show normalization of vessel
diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between
sickling and microvascular function in sickle cell disease.