Arterial iron regulates vasodilation during anemia via endothelial holo-alpha globin

Iron deficiency is a highly prevalent nutrient deficiency and the most common cause of anemia. Although iron deficiency exacerbates cardiovascular disease, the direct impact of iron deficiency on the vasculature remains unstudied. We assessed iron levels across the vascular endothelium and found resistance artery endothelial cells to have the lowest iron stores suggesting they may be especially impacted by iron deficiency. Anemia has previously been shown to increase arterial NO signaling in patients, and we have previously shown endothelial -globin (Hb) scavenges nitric oxide (NO) in the resistance artery endothelium. We hypothesize iron regulates vascular function through downregulation of endothelial Hb. To test this, we used a novel model of iron deficiency anemia (IDA). In female mice, IDA increased NO signaling which was rescued to control levels by repletion of vascular iron with ferric dextran. Despite being similarly anemic and having a similar reduction in Hb protein, there were no changes in NO signaling across groups in male mice. We further measured whether Hb was in its heme-bound (holo-Hb) or heme-free (apo-Hb) state and found males did not fully lose holo-Hb. Using endothelial specific Hb knockout mice, we show loss of endothelial Hb is necessary for increased NO signaling in IDA and for the rescue of NO signaling by ferric dextran in female mice. Altogether the data presented here demonstrate iron modulates endothelial NO signaling through the regulation of Hb.