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Comment on: Heme, the HO–CO–sGC–cGMP pathway, and corpus cavernosum contractility: new insights into the pathophysiology of priapism in sickle cell disease

International Journal of Impotence Research (2025)Cite this article

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Priapism, particularly recurrent ischemic priapism (RIP), remains one of the most challenging complications of SCD, affecting up to 40% of male patients and leading to erectile dysfunction in a substantial proportion [2, 3]. While excessive nitric oxide–cGMP signaling and impaired phosphodiesterase type 5 (PDE5) regulation have been established as central contributors [3], the contribution of contractile mechanisms has been less well characterized. This study by Pereira et al. [1] fills an important gap by demonstrating that excess extracellular heme blunts sympathetic and receptor-mediated contractility of the corpus cavernosum.

The methodological approach—using electrical field stimulation, phenylephrine, and a depolarizing concentration of potassium chloride (KCl) to probe neurogenic, receptor-dependent, and receptor-independent contraction, respectively—is rigorous and comprehensive. The consistent attenuation of contractile responses across all modalities strengthens the conclusion that heme profoundly impairs the ability of cavernosal smooth muscle to maintain flaccidity. Importantly, the reversal of these effects by HO and sGC inhibition confirms pathway specificity. These observations align with vascular studies demonstrating that CO derived from heme metabolism acts as a potent vasorelaxant [4, 5] but extend this knowledge into the penile circulation and erectile tissue.

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Fig. 1: Heme-mediated signaling pathway contributing to ischemic priapism through inhibition of smooth muscle contraction in the corpus cavernosum (left).
Fig. 2

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Acknowledgements

The authors of this commentary are funded by the National Institutes of Health (DK-132948), the University of South Carolina Institute for Cardiovascular Disease Research and the Airforce Office of Scientific Research, U.S. Airforce, Department of Defense.

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Authors and Affiliations

  1. Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC, USA

    Fernanda Priviero & R Clinton Webb

  2. Department of Biomedical Engineering, Molinaroli College of Engineering and Computing, University of South Carolina, Swearingen Engineering Center, Columbia, SC, USA

    Fernanda Priviero & R Clinton Webb

  3. Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, USA

    Fernanda Priviero & R Clinton Webb

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  1. Fernanda Priviero
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  2. R Clinton Webb
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FP and RCW contributed equally to the creation of this scholarly work.

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Correspondence to Fernanda Priviero.

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Priviero, F., Webb, R.C. Comment on: Heme, the HO–CO–sGC–cGMP pathway, and corpus cavernosum contractility: new insights into the pathophysiology of priapism in sickle cell disease. Int J Impot Res (2025). https://doi.org/10.1038/s41443-025-01203-6

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