(A and B) Images showing how reduction in density of extracellular matrix can improve tumor perfusion and oxygen delivery. (C and D) Metronomic antiangiogenic therapy can normalize vasculature by promoting vascular maturation. Among other effects, this treatment can reduce disparities in vessel diameter at bifurcation points. Since flow resistance is proportional to the vessel radius raised to the fourth power, small differences in the diameter of daughter vessels leads to large effects on flow distribution. (C) Discrepancy in vessel diameters causes vascular hypoxia in a daughter vessel. (D) Normalization restores equal flow distribution to both daughter vessels, eliminating hypoxia. (E) Theoretical demonstration of relative efficiencies of tumor hypoxia reduction by varying breathing gas O2 concentration for human versus rodent hemoglobin. These simulations were done using a Green’s function approach to calculate the oxygen field in a 3D region of a tumor growing in a skin-flap window chamber (17). Experimentally determined input variables include 3D vascular network structure, flow velocity and hematocrit of all vessel segments, vascular pO2 throughout the network, and oxygen consumption rate. Baseline arterial pO2 is 100 mmHg under air breathing conditions. At baseline the hypoxic fraction (defined as pO2 <10 mmHg) is around 47% for both hemoglobins. As arterial pO2 increases, the hypoxic fraction decreases for both hemoglobins. However, the rate at which the hypoxic fraction drops is greater for rodent hemoglobin (P50 = 40 mmHg), than human hemoglobin (P50 = 26 mmHg). Note that complete elimination of hypoxia cannot be achieved at the clinical limit of 3 atmospheres O2 for either hemoglobin, but the relative difference in remaining hypoxia is higher for human hemoglobin. These results strongly suggest that solely increasing oxygen content of blood is insufficient to eliminate hypoxia. Combining high O2 content breathing with strategies such as those described in A–D would be more likely to successfully mitigate hypoxia.