The Effects of Combined Cyclic Stretch and Pressure on the Aortic Valve Interstitial Cell Phenotype

• Authors: Patrick Thayer, Georgia Institute of Technology; Kartik Balachandran, Georgia Institute of Technology; Swetha Rathan, Georgia Institute of Technology; Choon Hwai Yap, Georgia Institute of Technology; Sivakkumar Arjunon, Georgia Institute of Technology; Hanjoong Jo, Emory University; Ajit Yoganathan, Emory University
• Journal Title: Annals of Biomedical Engineering
• Volume: Volume 39, Number 6
• Publisher: Springer Verlag (Germany) | 2011-06-01, Pages 1654-1667
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s10439-011-0273-x
• Subjects: Engineering, Biomedical; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Technology; Engineering, Biomedical; Engineering; ENGINEERING, BIOMEDICAL; Aortic valve; Stretch; Pressure; Phenotype; BIOLOGICAL-PROPERTIES; ACTIN POLYMERIZATION; DEPENDENT MANNER; SMOOTH-MUSCLE; HEART-VALVES; EX-VIVO; CALCIFICATION; FILAMENTS; CALPONIN; CYTOSKELETON

Abstract

Aortic valve interstitial cells (VIC) can exhibit phenotypic characteristics of fibroblasts, myofibroblasts, and smooth muscle cells. Others have proposed that valve cells become activated and exhibit myofibroblast or fibroblast characteristics during disease initiation and progression; however, the cues that modulate this phenotypic change remain unclear. We hypothesize that the mechanical forces experienced by the valve play a role in regulating the native phenotype of the valve and that altered mechanical forces result in an activated phenotype. Using a novel ex vivo cyclic stretch and pressure bioreactor, we subjected porcine aortic valve (AV) leaflets to combinations of normal and pathological stretch and pressure magnitudes. The myofibroblast markers α-SMA and Vimentin, along with the smooth muscle markers Calponin and Caldesmon, were analyzed using immunohistochemistry and immunoblotting. Tissue structure was analyzed using Movat's pentachrome staining. We report that pathological stretch and pressure inhibited the contractile and possibly myofibroblast phenotypes as indicated by downregulation of the proteins α-SMA, Vimentin, and Calponin. In particular, Calponin downregulation implies depolymerization of actin filaments and possible conversion to a more synthetic (non-contractile) phenotype. This agreed well with the increase in spongiosa and fibrosa thickness observed under elevated pressure and stretch that are typically indicative of increased matrix synthesis. Our study therefore demonstrates how cyclic stretch and pressure may possibly act together to modulate the AVIC phenotype. © 2011 Biomedical Engineering Society.