title: 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 (10-7M), 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.
authors.affiliation: Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Perez
authors.affiliation: Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Diaz
authors.affiliation: Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA.
authors.forename: Ishita
authors.initials: I
authors.lastname: Tandon
authors.affiliation: Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Plate
authors.affiliation: Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Martindale
authors.affiliation: Department of Biomedical Engineering, University of Arkansas, 122 John A. White Jr. Engineering Hall, Fayetteville, AR, 72701, USA. kbalacha@uark.edu.
authors.forename: Kartik
authors.initials: K
authors.lastname: Balachandran
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D024022:Fibrillar Collagens / Q000378:metabolism; D005355:Fibrosis; D006349:Heart Valve Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008810:Mice, Inbred C57BL; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D012701:Serotonin / Q000633:toxicity*; D013318:Stroke Volume / Q000187:drug effects; D034421:Sus scrofa; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D024022:Fibrillar Collagens; D044140:Receptor, Angiotensin, Type 1; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D000804:Angiotensin II; D012701:Serotonin
keywords: Angiotensin-II; Cell contractility; Serotonin; Valve interstitial cell; Valve remodeling