Improvements in RBC oxygen saturation and flow rheology under low oxygen in blood from SCD mice treated with MetAP2 inhibitor. Pooled whole blood from Townes SCD mice treated for 3 days intraperitoneally with CKD-732 or ZGN-1061 (1 mg/kg, twice daily) or vehicle control (n = 5 in each pool) were compared. (A) Single-cell oxygen saturation as a function of oxygen partial pressure was determined,²⁹  and frequency histograms of 2 treated pools compared with the vehicle pool for 4.5%, 6.4%, and 7.8% O₂. The red vertical lines are placed on the median percentage of oxygen saturation values of the vehicle pool and show a similar shift by both MetAP2 inhibitors to higher levels of saturation. Red arrows indicate the bimodal distribution of oxygen saturation, including a population of cells with low oxygen saturation that is absent in the treated pools (complete histograms for all pO₂ values, including hypoxia and normoxia controls, are shown as supplemental Figure 5). (B) Median percentage of oxygen saturation values for the vehicle pool compared with the CKD-732–treated pool shows improved oxygen saturation at all oxygen partial pressures. Similar results were obtained in 2 independent studies. (C) Individual blood samples from mice treated with CKD-732 and controls were tested in an assay of oxygen-dependent blood flow rheology.^30,31  Oxygen threshold to lower blood flow is significantly decreased in MetAP2 inhibitor–treated blood samples containing modified HbS. *P = .026, 2-tailed Student t test. (D) Total observed blood flow velocity drop, when transitioning from 21% to 0% oxygen, is significantly lower. *P = .011, 2-tailed Student t test. Similar results were obtained in 2 independent studies.