Endothelial function: cardiovascular disease and erectile dysfunction
The endothelium is a thin layer of specialized cells that lines the lumen of arteries and veins. It is a real organ that regulates numerous functions including:
- Semipermeable barrier, to regulate the passage of substances from the blood to extracellular fluids and vice versa
- Angiogenesis and vascular remodelling, i.e. formation of new capillaries and compensation circles
- Fluidity of the blood, through the regulation of coagulation, fibrinolysis and aggregation of platelets
- Inflammation, regulating the adhesion and activation of circulating leukocytes
- Oxidation of lipoproteins and their deposition in the wall of the vessels
When one or more of these functions is compromised we speak about endothelial dysfunction, a pathological condition that affects all organs but with more evident consequences on cardiac health and, in men, on erectile function.
Cardiovascular disease
Endothelial dysfunction is the most important factor in the development of atherosclerosis, that is, the narrowing of the cardiac arteries by intramural lipid deposition. Endothelial anomalies in fact cause inflammatory phenomena with adhesion of leukocytes and activation of inflammation and oxidation of circulating lipoproteins that overcome the endothelial barrier and form accumulations. The presence of dyslipidaemia (increase of cholesterol and LDL) accelerates this process and the most used treatment is precisely the reduction of cholesterol, for example with statins. However, individuals with very low circulating lipids can still develop atherosclerosis if endothelial inflammation is present as well as increased lipids do not cause deposits if inflammation is not present. In summary, the ideal treatment of atherosclerosis and ischemic heart disease is the correction of endothelial dysfunction.
H2S, in concert with nitric oxide (NO) and carbon monoxide (CO), is one of the main players in vasodilation and neo-angiogenesis and is also involved in the regulation of coagulation and platelet activation. All these activities indicate a primary role of H2S deficiency in endothelial dysfunction. In fact, experimental data confirm the potential benefit of H2S support strategies in atherosclerosis, and in cardiovascular diseases.
References:
Citi V et al. Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches. J Adv Res, May 2020 https://www.sciencedirect.com/science/article/pii/S2090123220300989
Kanagy NL et al. Vascular biology of hydrogen sulfide. Am J Physiol Cell Physiol 312: C537–C549, 2017. https://journals.physiology.org/doi/pdf/10.1152/ajpcell.00329.2016
Greaney JL et al. Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in
Hypertensive Adults. Hypertension Volume 69, Issue 5, May 2017, Pages 902-909. https://www.ahajournals.org/doi/epub/10.1161/HYPERTENSIONAHA.116.08964
Sun H-J et al. Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front Pharmacol. 2019; 10: 1568. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985156/
Wu D et al. An Update on Hydrogen Sulfide and Nitric Oxide Interactions in the Cardiovascular System. Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 4579140, 16.pages https://www.hindawi.com/journals/omcl/2018/4579140/
Pan L-L et al. The Role of Hydrogen Sulfide on Cardiovascular Homeostasis: An Overview with Update on Immunomodulation. Front Pharmacol. 2017; 8: 686. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622958/
Erectile dysfunction
Erectile dysfunction is the inability to obtain and / or maintain a penile erection sufficient to complete satisfactory sexual intercourse. The release of H2S by the endothelium and perivascular muscle cells of the corpora cavernosa is essential for correct erectile function. It cooperates with nitric oxide (NO) in inducing and maintaining the erection following sexual arousal and may even compensate a relative deficit of NO. In experimental models the delivery of H2S efficiently corrects erectile dysfunction. H2S is also an inhibitor of PDE5 and ay sinergize with the drugs commonly used for the disease. Treatments for erectile dysfunction based on a support to H2S have been proposed as a complementation or substitution to PDE5 inhibitors (e.g. sildenafil) but no H2S-supporting drugs for human use were available so far.
References:
d’Emmanuele di Villa Bianca R et al. Hydrogen sulfide and erectile function: a novel therapeutic target. Nature Reviews Urology volume 8, pages 286–289(2011). https://www.nature.com/articles/nrurol.2011.45
Qiu X et al. Role of Hydrogen Sulfide in the Physiology of Penile Erection. J Androl. 2012 ; 33(4): 529–535. https://onlinelibrary.wiley.com/doi/full/10.2164/jandrol.111.014936
La Fuente JM et al. Erectile dysfunction is associated with defective L-cysteine/hydrogen sulfide pathway in human corpus cavernosum and penile arteries [published online ahead of print, 2020 Jul 23]. Eur J Pharmacol. 2020;173370. https://pubmed.ncbi.nlm.nih.gov/32712093/
La Fuente JM et al. L-cysteine/hydrogen sulfide pathway induces cGMP-dependent relaxation of corpus cavernosum and penile arteries from patients with erectile dysfunction and improves arterial vasodilation induced by PDE5 inhibition. Eur J Pharmacol. 2019 Nov 15;863:172675. https://pubmed.ncbi.nlm.nih.gov/31542487/
Jupiter RC et al. Analysis of erectile responses to H2S donors in the anesthetized rat. Am J Physiol Heart Circ Physiol. 2015 Sep; 309(5): H835–H843. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591400/
Anak GY et al. Hydrogen sulfide compensates nitric oxide deficiency in murine corpus cavernosum. Pharmacol Res 2016 Nov;113(Pt A):38-43. https://pubmed.ncbi.nlm.nih.gov/27521839/
Evolution of atherosclerosis