Grant Brewing – Luke Dunaway

Iron regulation of tissue perfusion

Both iron deficiency (ID) and endothelial dysfunction are associated with chronic diseases such as heart failure and chronic kidney disease (CKD). However, how iron regulates endothelial functions remains largely unstudied. Iron deficiency can be categorized as either absolute iron deficiency, in which serum iron and tissue iron are depleted, or functional iron deficiency, in which iron is sequestered intracellularly and unavailable for erythropoiesis. My preliminary data suggests endothelial iron stores are depleted in absolute iron deficiency but are increased in functional iron deficiency. Therefore, the cardiovascular consequences of these two forms of iron deficiency are likely distinct. One of the primary functions of the endothelium is to regulate tissue perfusion via modulating vascular tone and vascular density. The central hypothesis of the proposed studies is that absolute and functional iron deficiency dysregulate tissue perfusion through disruption of vascular tone and microvascular density. Specifically, we propose two aims. Aim 1: Absolute iron deficiency dysregulates endothelial nitric oxide by suppressing a-globin expression and maturation. In homeostatic conditions, a-globin (Hba) is expressed uniquely in resistance arteries and regulates the scavenging and production of nitric oxide. Our preliminary data suggest iron is an important regulator of endothelial Hba and therefore vascular tone. Aim 2: Functional iron deficiency drives endothelial iron accumulation thereby contributing to the cardiovascular etiology of CKD. Activating transcription factor 4 (ATF4) is well-established as an iron-responsive regulator of erythrocyte development and has recently been implicated in regulating microvascular density provoking the hypothesis that functional iron deficiency drives microvascular rarefaction in CKD via loss of ATF4. The long-term goal of this project is to provide novel insights into the mechanisms by which iron regulates endothelial function and allow us to better understand the vascular etiologies of chronic disease.

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Post Doctoral Fellow, CVRC, Isakson lab, University of Virginia, Charlottesville Va