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

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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 (10−7 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.

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Acknowledgments

The study was funded by the University of Arkansas Honors College Grant and Arkansas Biosciences Institute. We also thank Dr. Zaharoff and his graduate students at the University of Arkansas for their assistance with the in vivo mouse model.

Conflict of interest

All authors declare no competing interests.

Human Studies

No human studies were carried out by the authors for this article.

Animal Studies

All in vivo mouse experiments were approved by the Institutional Animal Care and Use Committee at the University of Arkansas and conducted in accordance with the NIH Guide for Care and Use of Laboratory Animals (National Research Council). Pig hearts from the abattoir were obtained and used in accordance with local regulations and with the approval of the University of Arkansas.

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  1. Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA

    Jessica Perez, Nancy Diaz, Ishita Tandon, Rachel Plate, Christopher Martindale & Kartik Balachandran

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  1. Jessica Perez
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  2. Nancy Diaz
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Correspondence to Kartik Balachandran.

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Associate Editors Hanjoong Jo, Craig A. Simmons, and Ajit P. Yoganathan oversaw the review of this article.

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Perez, J., Diaz, N., Tandon, I. et al. Elevated Serotonin Interacts with Angiotensin-II to Result in Altered Valve Interstitial Cell Contractility and Remodeling. Cardiovasc Eng Tech 9, 168–180 (2018). https://doi.org/10.1007/s13239-017-0298-x

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