Estrogen modulates serotonin effects on vasoconstriction through Src inhibition

• Published in: Experimental & molecular medicine Vol. 50; no. 12; pp. 1 - 9
• Main Authors: Kim, Jae Gon, Leem, Young-Eun, Kwon, Ilmin, Kang, Jong-Sun, Bae, Young Min, Cho, Hana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.12.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 17β-Estradiol; 631/443/592/75/243/785; 631/80/86/2363; 82/80; 9/74; Animals; Aorta; Aorta - pathology; Arteries; Biomedical and Life Sciences; Biomedicine; Contractility; Contraction; Down-Regulation; Estrogens - metabolism; HEK293 Cells; Humans; Hyperreactivity; Male; Medical Biochemistry; Mesenteric Arteries - pathology; Molecular Medicine; Muscle contraction; Myocytes; Organ Culture Techniques; Patch-Clamp Techniques; Potassium Channels, Voltage-Gated - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Estrogen - metabolism; Rodents; Serotonin; Serotonin - metabolism; Smooth muscle; src-Family Kinases - metabolism; Stem Cells; Tamoxifen; Vasoactive agents; Vasoconstriction; Vasoconstriction - physiology; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-018-0193-z

Estrogen has diverse effects on cardiovascular function, including regulation of the contractile response to vasoactive substances such as serotonin. The serotonin system recently emerged as an important player in the regulation of vascular tone in humans. However, hyperreactivity to serotonin appears to be a critical factor for the pathophysiology of hypertension. In this study, we examined the modulatory mechanisms of estrogen in serotonin-induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17β-Estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aortic strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes are not mediated by estrogen receptor. Patch-clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which was significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK293T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerts vasodilatory effects on serotonin-precontracted arteries via Src, implying a critical role for estrogen in the prevention of vascular hyperreactivity to serotonin. Vascular disease: estrogen suppresses artery-constricting effect of serotonin Estrogen helps lower blood pressure by blocking a key signaling protein that the neurotransmitter serotonin normally activates to promote the constriction of blood vessels. A team from South Korea led by Hana Cho from Sungkyunkwan University School of Medicine, Suwon, and Young Min Bae from Konkuk University School of Medicine, Chungju, showed that estradiol, a type of estrogen steroid hormone, spurred a relaxation of serotonin-induced constriction in rat artery tissue, but the effect was not mediated through the estrogen receptor. Instead, the researchers showed in rat tissue and human cells that an enzyme called Src was essential: serotonin increased Src activity in the muscle cells that contract during arterial narrowing, while estradiol inhibited Src function. The findings could help inform future therapies for vascular diseases.