Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice

Abstract

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 α-and β S -globins with <1% γ-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 + γ mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + γ 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.

The proverbial chicken or the egg? Dissection of the role of cell-free hemoglobin versus reactive oxygen species in sickle cell pathophysiology

“…The authors confirm their previous findings of compensatory increases in eNOS and cyclooxygenase-2 protein expression in the sickle cell transgenic mouse, as well as increased baseline arteriolar vasodilation (15), indicating a potential compensatory upregulation of non-NO-dependent vasodilators (prostacyclin) in response to diminished NO bioavailability.…”

“…The assessment of vascular reactivity in the sickle cell transgenic mouse revealed significantly blunted responses to both acetylcholine (ACh) and SNP, as well as blunted changes in mean arterial pressure (MAP) in response to N G -nitro-Larginine methyl ester (L-NAME), consistent with a global impairment in the NO axis and, more specifically, a resistance to NO vasodilatory activity (evidenced by the lack of response to an exogenous NO donor) (13,15). The authors confirm their previous findings of compensatory increases in eNOS and cyclooxygenase-2 protein expression in the sickle cell transgenic mouse, as well as increased baseline arteriolar vasodilation (15), indicating a potential compensatory upregulation of non-NO-dependent vasodilators (prostacyclin) in response to diminished NO bioavailability.…”

Pathophysiology and therapy for haemoglobinopathies; Part I: sickle cell disease

“…These may be upregulated as a compensatory mechanism for lack of NO responsiveness (Ref. 84). Kaul et al also studied BERK + γ − transgenic mice, which produce 80% HbS and 20% HbF as opposed to only HbS.…”

Sickle Cell Anemia: Conclusions from a Forensic Case Report of a Young African Woman Who Died After Anesthesia

“…These include higher sickle cell adhesion to endothelial cells, higher viscosity and lower deformability of sickle cell membranes, and altered intracellular viscosity of the affected cells. The rheological abnormalities further result in altered vascular endothelial regulation possibly transmitted by nitric oxide and reactive oxygen species [15][16][17].…”