Microvascular response to cell free Hb infusion in transgenic mouse model of sickle cell anemia

Abstract

Targeting O2 delivery to anoxic regions may reduce the incidence of complete deoxygenation of the RBC and thus be an effective therapy in sickle cell disease. Knockout transgenic mice (n = 6) were treated with an infusion of MP4, a blood substitute that targets oxygen delivery to hypoxic areas (malemide polyethylene glycol‐conjugated Hb, Hemospan®, Sangart Inc., San Diego, CA) and then subjected to a hypoxic challenge (FiO2 = 0.08). Results were compared to a control group which received saline (n = 5). A 10% blood volume (BV) topload was infused (BV estimated as 6% body weight). Changes of microvessel diameter and functional capillary density (number of capillaries perfused per area of tissue) were studied in vivo using the dorsal skin fold window chamber model. Mean arterial pressure was higher after treatment during normoxia and hypoxia challenge as compared to the control group. Arterioles dilated and venules remained unchanged from baseline during hypoxia in both study groups. FCD was statistically reduced from baseline during hypoxia; however MP4 infused animals maintained FCD at a level that was statistically higher than observed with saline infusion; 60 ± 15% and 27 ± 24%, respectively. Thus MP4 treatment reduces the severity of hypoxia‐mediated decline in FCD. Mechanistically the higher FCD could be due to the higher perfusion pressure in the absence of vasoconstriction. Reduced sickling and inflammatory responses (i.e., lesser leukocyte‐adhesion) are likely concomitant mechanisms which support and enhance capillary perfusion.