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Functional Coupling of Valvular Interstitial Cells and Collagen Via α2β1 Integrins in the Mitral Leaflet

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Abstract

Once considered passive flaps, we now understand that mitral leaflets are dynamic structures with their own vasculature and innervation that actively remodel and even generate force in response to their environments. Valvular interstitial cells (VICs) are contractile and could underlie mitral leaflet force generation, but the exact mechanisms for VICs in mitral leaflet force generation are not understood. This study tested the hypothesis that actin-mediated VIC force generation coupled to collagen via α2β1 integrins is necessary for force generation in the mitral leaflet. High magnification fluorescent imaging of freshly excised porcine mitral leaflets revealed VIC cytoplasm tightly conforming to collagen fibers, with actin within VIC cytoplasmic processes appearing to attach to the collagen fibers. Functional studies of isometric force development demonstrated that while control samples developed force in response to KCl, either blocking α2β1 integrins or blocking actin polymerization via cytochalasin abolished KCl-induced force development (p < 0.001). These results strongly suggest that VIC-collagen coupling, mediated by α2β1 integrins, is necessary for KCl-induced force generation in the mitral leaflet. This functional coupling between collagen and VICs via α2β1 integrins may play a role for in vivo mitral valve function.

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Acknowledgments

The authors wish to acknowledge all the members of the Stanford Cardiovascular Surgical Physiology Research Laboratory, especially Kathy N. Vo and Paul Chang, as well as microscopy assistance from Kitty Lee, Dr. Robert Raphael, and John Wright, and machining assistance from Dwight Dear. The authors also wish to thank Dr. L. Scott Baggett for his statistical expertise. Funding for this project came in part from an AATS Summer Internship Scholarship (EHS), as well as a Hertz Foundation Graduate Fellowship (EHS), NIH Ruth-Kirschstein (F30) National Research Service Award (EHS), and a Post-Doctoral Fellowship from the Western States Affiliate of the American Heart Association (JCS).

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Drive, Stanford, CA, 94305-5247, USA

    Julia C. Swanson, Neil B. Ingels Jr. & D. Craig Miller

  2. Department of Cardiovascular Physiology and Biophysics, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA, USA

    Neil B. Ingels Jr. & D. Craig Miller

  3. Department of Bioengineering, Rice University, Houston, TX, USA

    Elizabeth H. Stephens, Christopher A. Durst & K. Jane Grande-Allen

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  1. Elizabeth H. Stephens
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  4. K. Jane Grande-Allen
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  5. Neil B. Ingels Jr.
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Correspondence to D. Craig Miller.

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Associate Editor Chwee Teck Lim oversaw the review of this article.

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Stephens, E.H., Durst, C.A., Swanson, J.C. et al. Functional Coupling of Valvular Interstitial Cells and Collagen Via α2β1 Integrins in the Mitral Leaflet. Cel. Mol. Bioeng. 3, 428–437 (2010). https://doi.org/10.1007/s12195-010-0139-6

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