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Cellular-scale sex differences in extracellular matrix remodeling by valvular interstitial cells

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Abstract

Males acquire calcific aortic valve disease (CAVD) twice as often as females, yet stenotic valves from females display significantly higher levels of fibrosis compared to males with similar extent of disease. Fibrosis occurs as an imbalance between the production and degradation of the extracellular matrix (ECM), specifically type I collagen. This work characterizes ECM production and remodeling by male and female valvular interstitial cells (VICs) to better understand the fibrocalcific divergence between sexes evident in CAVD. Male and female VICs were assessed for gene and protein expression of myofibroblastic markers, ECM components, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) via qRT-PCR and western blot. Overall metabolic activity was also measured. Activity assays for collagenase and gelatinase were performed to examine degradation behavior. Male VICs produced greater levels of myofibroblastic markers while female VICs showed greater metabolic activity and collagen production. In general, females displayed a greater level of MMP expression and production than males, but no sex differences were observed in TIMP production. Male VICs also displayed a greater level of collagenase and gelatinase activity than female VICs. This work displays sex differences in ECM remodeling by VICs that could be related to the sexual dimorphism in ECM structure seen in clinical CAVD.

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Acknowledgements

Not applicable.

Funding

This work was supported by grants from the NIH (R01 HL141181 and R21 EB019508 to K.S.M. and TL1TR002375 to A.J.S.) and the UW-Madison Graduate Engineering Research Scholars (GERS) Program. This material is based upon work supported by the National Science Foundation under Grant No. 1400815. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Wisconsin-Madison, 1111 Highland Ave, WIMR 8531, Madison, WI, 53705, USA

    LaTonya R. Simon, Lysmarie Figueroa Rios, Joshua Zembles & Kristyn S. Masters

  2. Cellular and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Ashley J. Scott & Kristyn S. Masters

  3. Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA

    Kristyn S. Masters

  4. Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Kristyn S. Masters

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  1. LaTonya R. Simon
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Contributions

LS, AS, LFR, JZ, and KM participated in study design and data analysis. LS, AS, and KM drafted the final manuscript.

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Correspondence to Kristyn S. Masters.

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No animal or human subjects were used in this work. All cells were derived from surplus animal tissues acquired from a local butcher.

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Simon, L.R., Scott, A.J., Figueroa Rios, L. et al. Cellular-scale sex differences in extracellular matrix remodeling by valvular interstitial cells. Heart Vessels 38, 122–130 (2023). https://doi.org/10.1007/s00380-022-02164-2

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  • DOI: https://doi.org/10.1007/s00380-022-02164-2

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