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REVIEW article

Front. Physiol.
Sec. Vascular Physiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1545044
This article is part of the Research Topic Insights in Vascular Physiology: 2024 View all 5 articles

Promotion of Nitric Oxide Production: Mechanisms, Strategies, and Possibilities

Provisionally accepted

The final, formatted version of the article will be published soon.

    The discovery of nitric oxide (NO) and the role of endothelial cells (ECs) in its production has revolutionized medicine. NO can be produced by isoforms of NO synthases (NOS), including the neuronal (nNOS), inducible (iNOS), and endothelial isoforms (eNOS), and via the non-classical nitrate-nitrite-NO pathway. In particular, endothelium-derived NO, produced by eNOS, is essential for cardiovascular health.Endothelium-derived NO activates soluble guanylate cyclase (sGC) in vascular smooth muscle cells (VSMCs), elevating cyclic GMP (cGMP), causing vasodilation. Over the past four decades, the importance of this pathway in cardiovascular health has fueled the search for strategies to enhance NO bioavailability and/or preserve the outcomes of NO's actions. Currently approved approaches operate in three directions: 1) providing exogenous NO, 2) promoting sGC activity, and 3) preventing degradation of cGMP by inhibiting phosphodiesterase 5 activity. Despite clear benefits, these approaches face challenges such as the development of nitrate tolerance and endothelial dysfunction. This highlights the need for sustainable options that promote endogenous NO production. This review will focus on strategies to promote endogenous NO production. A detailed review of the mechanisms regulating eNOS activity will be first provided, followed by a review of strategies to promote endogenous NO production based on the levels of available preclinical and clinical evidence, and perspectives on future possibilities.

    Keywords: nitric oxide, eNOS, endothelium, preclinical evidence, clinical trials ABH, 2(S)-amino-6-hexanoic acid, ACh, acetylcholine, ADMA, Asymmetric dimethylarginine, AKT, protein kinase B, AMPK, AMP-activated protein kinase, ASL, argininosuccinate lyase, ASS, argininosuccinate synthase, BEC, S-(2-boronoethyl)-l-cysteine

    Received: 13 Dec 2024; Accepted: 07 Jan 2025.

    Copyright: © 2025 Gonzalez, Clayton, Wauson, Christian and Tran. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Quang-Kim Tran, Des Moines University, Des Moines, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.