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1 Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
2 Surgery and Biomedical Engineering, Duke University, Durham, NC, USA
3 Cardiovascular and Thoracic Surgery, Brown University, Providence, RI, USA
* To whom correspondence should be addressed. E-mail: msacks{at}pitt.edu.
It has been speculated that heart valve interstitial cells (VICs) maintain valvular tissue homeostasis through regulated ECM (primarily collagen) biosynthesis. Additionally, VICs appear to be phenotypically plastic as they transdifferentiate into myofibroblasts during times of valve development, disease, and remodeling. Under normal physiological conditions, the transvalvular pressures (TVPs) on the right and left side of the heart are vastly different. Hence, we hypothesize that the higher left side TVPs impose larger local tissue stresses on VICs, which increases their stiffness thru cytoskeletal composition, and that this relationship affects collagen biosynthesis. To evaluate this hypothesis, isolated ovine VICs from the four heart valves were subjected to micropipette aspiration to assess cellular stiffness, and cytoskeletal composition and collagen biosynthesis were quantified using surrogates smooth muscle 
-actin (SMA) and heat shock protein 47 (Hsp47), respectively. Results revealed that VICs from the aortic and mitral valves were significantly stiffer (p<0.001) than the pulmonary and tricuspid VICs. Additionally, left side isolated VICs contained significantly more (p<0.001) SMA and Hsp47 than the right side VICs. Mean VIC stiffness correlated well (r=0.973) with TVP; SMA and Hsp47 also correlated well (r=0.996) with one another. Moreover, assays were repeated for VICs in situ, and as with the in vitro results, the left side VIC protein levels were significantly greater (p<0.05). These findings suggest that VICs respond to local tissue stress by altering cellular stiffness (through SMA content) and collagen biosynthesis. This functional VIC stress-dependent biosynthetic relationship may be crucial to maintaining valvular tissue homeostasis and also prove useful in understanding valvular pathologies.
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