Iron regulation of endothelial function in iron deficiency and chronic kidney disease

Iron dysregulation exacerbates chronic diseases such as heart failure and chronic kidney disease (CKD). Both diseases are associated with endothelial dysfunction, but how iron dysregulation may impact endothelial function remains largely unstudied. We have previously shown endothelial a-globin (Hba) scavenges nitric oxide (NO), and our reanalysis of published human bulk RNA-seq data suggests renal failure promotes endocardial iron accumulation and increases Hba expression. Because Hba is regulated by iron in erythrocytes, we hypothesized iron regulates cardiovascular function through modulating endothelial Hba. To test if iron impacts endothelial Hba expression we developed a mouse model of iron deficiency anemia (IDA) in which we were able to replete vascular iron. C57BL/6 mice were fed an iron deficient or control diet, and anemia was further progressed by two phlebotomies. To replete vascular iron, a subset of IDA mice received iron dextran and experiments were conducted one week later. As intended, FeDex did not rescue the anemia but did rescue vascular iron as measured by ferritin light chain protein. NO signaling was measured using laser speckle contrast imaging to measure changes in blood flow in response an NO synthase inhibitor. IDA increased NO signaling which was rescued to control levels by repletion of vascular iron. We also found endothelial Hba expression was decreased in iron deficiency and rescued by iron repletion in the mesenteric and renal vasculature. To directly investigate the role of endothelial Hba, we repeated these studies in endothelial specific Hba knockout mice. Loss of endothelial Hba prevented the rescue of NO signaling by FeDex. These data suggest iron regulates vascular function through modulating Hba. To investigate the role of Hba in CKD, we fed mice either control or 0.2% adenine diets for 8 weeks. These mice are anemic as determined by a significant reduction in blood hemoglobin and hematocrit. Furthermore, en face imaging of mesenteric arteries demonstrates robust endothelial iron accumulation. These data are in agreement with the human bulk RNA-seq data and provoke the hypothesis that iron dysregulation in CKD promotes vascular dysfunction through dysregulation of Hba. University of Virginia Basic and Translational Research Training Grant T32 007284 (; NIH F32HL172605; NIH HL088554; LaunchPad; AHA Predoctoral Fellowship (MAL) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.