Unraveling the association between oxidative stress, nitric oxide signaling, and hypoxia inducible factor in chronic limb-threatening ischemia

Heart, Vessels and Transplantation · Published 2026-03-10 · DOI 10.24969/hvt.2026.633

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Abstract

Objective: Chronic limb-threatening ischemia (CLTI) is a serious medical condition characterized by decreased blood supply to the lower limbs, which causes tissue loss and amputation. The pathophysiology of CLTI has been associated with oxidative stress, nitric oxide (NO) imbalance, and the hypoxia-inducible factor (HIF) signaling pathway. This review focuses on how oxidative stress causes endothelial dysfunction, impairment of NO bioavailability, and HIF stability, subsequently aggravating tissue hypoxia and ischemia. Furthermore, this review explores the treatment implications of focusing on these pathways to enhance CLTI outcomes. The aim of the review was to explore the role of oxidative stress, NO imbalance, and HIF pathway dysregulation in CLTI pathophysiology and implications for treatment. Methods: PubMed, Google Scholar, E-library, and the websites of medical journals (Medicine, Biology, and Biochemistry) were used as electronic databases for the literature search. Overall, 109 articles out of the 214 that were initially discovered satisfied the inclusion requirements. Results: Oxidative stress contributes to CLTI progression via endothelial dysfunction, impaired nitric oxide bioavailability, and HIF stability, worsening tissue hypoxia and ischemia. Conclusion: Targeting oxidative stress, nitric oxide, and HIF pathways may enhance CLTI outcomes.

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Publication details

Year
2026

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