# Iron Regulation of Endothelial Hemoglobin Alpha

> **NIH NIH F32** · UNIVERSITY OF VIRGINIA · 2024 · $74,284

## Abstract

|| PROJECT SUMMARY
Iron is a critical micronutrient for hemoprotein maturation and redox signaling. Iron deficiency anemia
(IDA) is associated with heart failure, chronic kidney disease, and chronic inflammation. In all these disease
states, intravenous iron delivery is often used to replenish iron stores and improve patient outcomes. The use
of intravenous iron, however, can have harmful consequences causing patients to undergo periods of iron
overload and iron deficiency during treatment. Furthermore, each of these diseases is mediated in part by
endothelial dysfunction. Thus, deciphering the molecular mechanisms of iron homeostasis in the endothelium
provides a previously undefined framework for potential translation to important cardiovascular diseases. The
regulation of blood flow, a primary function of the endothelium, is reliant upon many hemoproteins, especially
hemoglobin alpha (Hba) in the microvasculature. In homeostatic conditions, Hba is expressed uniquely in the
resistance arteries and regulates the scavenging and production of nitric oxide. Hemoglobin is tightly regulated
by systemic iron homeostasis in erythrocytes, but it is not known how iron regulates Hba in endothelial cells.
Our preliminary data suggest iron is an important regulator of endothelial Hba. The central hypothesis of the
proposed studies is that the regulation of endothelial function by systemic iron homeostasis is dependent upon
intracellular iron and heme availability which work in conjunction to regulate Hba. In order to test this
hypothesis, we will use mouse models of iron overload and iron deficiency anemia. We will use endothelial
specific knockout of transferrin receptor 1 (an iron import protein) and FLVCR1a (a heme export protein) to
modulate endothelial iron and heme concentrations independent of systemic iron homeostasis. Changes in
blood flow and NO signaling will be assessed with laser speckle contrast imaging. To investigate the link
between iron import and Hba expression, we will utilize a peptide developed by our lab which increases blood
flow by disrupting the Hba/eNOS complex. Biochemical assays will be used to assess endothelial heme
concentrations and Hba maturation. 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 diseases.

## Key facts

- **NIH application ID:** 10825453
- **Project number:** 1F32HL172605-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Luke Stewart Dunaway
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 1
- **Project period:** 2024-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825453

## Citation

> US National Institutes of Health, RePORTER application 10825453, Iron Regulation of Endothelial Hemoglobin Alpha (1F32HL172605-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10825453. Licensed CC0.

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