Elevated Serotonin Interacts with Angiotensin-II to Result in Altered Valve Interstitial Cell Contractility and Remodeling

Abstract

While the valvulopathic effects of serotonin (5HT) and angiotensin-II (Ang-II) individually are known, it was not clear how 5HT and Ang-II might interact, specifically in the context of the mechanobiological responses due to altered valve mechanics potentiated by these molecules. In this context, the hypothesis of this study was that increased serotonin levels would result in accelerated progression toward disease in the presence of angiotensin-II-induced hypertension. C57/BL6 J mice were divided into four groups and subcutaneously implanted with osmotic pumps containing: PBS (control), 5HT (2.5 ng/kg/min), Ang-II (400 ng/kg/min), and 5HT + Ang-II (combination). Blood pressure was monitored using the tail cuff method. Echocardiography was performed on the mice before surgery and every week thereafter to assess ejection fraction. After three weeks, the mice were sacrificed and their hearts excised, embedded and sectioned for analysis of the aortic valves via histology and immunohistochemistry. In separate experiments, porcine valve interstitial cells (VICs) were directly stimulated with 5HT (10 M), Ang-II (100 nM) or both and assayed for cellular contractility, cytoskeletal organization and collagen remodeling. After three weeks, average systolic blood pressure was significantly increased in the 5HT, Ang-II and combination groups compared to control. Echocardiographic analysis demonstrated significantly reduced ejection fraction in Ang-II and the combination groups. H&E staining demonstrated thicker leaflets in the combination groups, suggesting a more aggressive remodeling process. Picrosirius red staining and image analysis suggested that the Ang-II and combination groups had the largest proportion of thicker collagen fibers. VIC orientation, cellular contractility and collagen gene expression was highest for the 5HT + Ang-II combination treatment compared to all other groups. Overall, our results suggest that 5HT and Ang-II interact to result in significantly detrimental alteration of function and remodeling in the valve.

Editorial: Special Issue on Heart Valve Mechanobiology

“…The final two papers in this special issue consider the role of the activated myofibroblast in these contexts. In the first, Perez et al [32] used a combination of mouse models and novel in vitro approaches to report for the first time the effects of serotonin (associated with drug-induced valve disease and known to be mechanosensitive) in a context of hypertension (induced by angiotensin-II (Ang-II) treatment) on valve disease and VIC function. They found that combined serotonin and Ang-II treatment resulted in the worst cardiac function, thicker leaflets with more collagen, and greater VIC activation, as indicated by increased contractility and collagen gene expression.…”

Telotristat ethyl reverses myxomatous changes in mice mitral valves

“…The effects of serotonin, A2 and their combination on heart valves were studied previously in mice, where both in vivo and in vitro models were recruited ( 46 ). In their study, either serotonin or A2 administration elevated blood pressure and contributed to valve thickening, ECM remodeling and myofibroblastic transformation.…”

Molecular Similarity Relating to a Peptide Sequence Common toAngiotensin II (ANGII) and SARS-Cov2 S-Protein

“…Data obtained from rodent and cell culture systems demonstrate significant interaction between the serotonin and angiotensin systems. Serotoninergic dorsal raphe nucleus neurons are targets of ANGII; combined 5-HT/ANGII infusion reduces echocardiogram ejection fractions, causing a more aggressive remodeling of valves; blunting of platelet aggregation responses by ANGII relates to loss of the 5-HT transporter (SERT) [35][36][37].…”