Peripheral 5-HT/HTR6 axis is responsible for obesity-associated hypertension

• Published in: Biochimica et biophysica acta. Molecular cell research 2024-02, Vol.1871 (2), p.119651-119651, Article 119651
• Main Authors: Chechekhin, Vadim I, Ivanova, Anastasia M, Kulebyakin, Konstantin Y, Antropova, Yulia G, Karagyaur, Maxim N, Skryabina, Maria N, Chechekhina, Elizaveta S, Basalova, Natalia A, Grigorieva, Olga A, Sysoeva, Veronika Yu, Kalinina, Natalia I, Tkachuk, Vsevolod A, Tyurin-Kuzmin, Pyotr A
• Format: Article
• Language: English
• Subjects: Humans; Hypertension - etiology; Norepinephrine - pharmacology; Obesity - complications; Protein Isoforms; Serotonin
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2023.119651

Hypertension is one of the major life-threatening complications of obesity. Recently adipose multipotent mesenchymal stromal cells (MSCs) were implicated to the pathogenesis of obesity-associated hypertension. These cells amplify noradrenaline-induced vascular cell contraction via cAMP-mediated signaling pathway. In this study we tested the ability of several cAMP-mediated hormones to affect the adrenergic sensitivity of MSCs and their associated contractility. Despite that adipose MSCs express a plethora of receptors capable of cAMP signaling activation, only 5-HT was able to elevate α1A-adrenoceptor-induced Ca signaling in MSCs. Furthermore, 5-HT markedly enhanced noradrenaline-induced MSCs contractility. Using HTR isoform-specific antagonists followed by CRISPRi-mediated knockdown, we identified that the observed 5-HT effect on MSCs was mediated by the HTR6 isoform. This receptor was previously associated exclusively with 5-HT central nervous system activity. Discovered effect of HTR6 on MSCs contractility points to it as a potential therapeutic target for the prevention and treatment of obesity-associated hypertension.