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Extracellular Matrix Rigidity Modulates Human Cervical Smooth Muscle Contractility—New Insights into Premature Cervical Failure and Spontaneous Preterm Birth

Reproductive Sciences volume 28, pages 237–251 (2021)Cite this article

Abstract

Spontaneous preterm birth (sPTB), a major cause of infant morbidity and mortality, must involve premature cervical softening/dilation for a preterm vaginal delivery to occur. Yet, the mechanism behind premature cervical softening/dilation in humans remains unclear. We previously reported the non-pregnant human cervix contains considerably more cervical smooth muscle cells (CSMC) than historically appreciated and the CSMC organization resembles a sphincter. We hypothesize that premature cervical dilation leading to sPTB may be due to (1) an inherent CSMC contractility defect resulting in sphincter failure and/or (2) altered cervical extracellular matrix (ECM) rigidity which influences CSMC contractility. To test these hypotheses, we utilized immunohistochemistry to confirm this CSMC phenotype persists in the human pregnant cervix and then assessed in vitro arrays of contractility (F:G actin ratios, PDMS pillar arrays) using primary CSMC from pregnant women with and without premature cervical failure (PCF). We show that CSMC from pregnant women with PCF do not have an inherent CSMC contractility defect but that CSMC exhibit decreased contractility when exposed to soft ECM. Given this finding, we used UPLC-ESI-MS/MS to evaluate collagen cross-link profiles in the cervical tissue from non-pregnant women with and without PCF and found that women with PCF have decreased collagen cross-link maturity ratios, which correlates to softer cervical tissue. These findings suggest having soft cervical ECM may lead to decreased CSMC contractile tone and a predisposition to sphincter laxity that contributes to sPTB. Further studies are needed to explore the interaction between cervical ECM properties and CSMC cellular behavior when investigating the pathophysiology of sPTB.

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Data Availability

All raw data are available upon request.

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Funding

This project was supported by the National Institutes of Health Grants (K08HD088758 and 1R01HD082251 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development), the Louis V. Gerstner Jr. Scholars Program and the March of Dimes Prematurity Research Center at the University of Pennsylvania, Philadelphia, PA. These funding sources had no involvement in the study design, collection, analysis or interpretation of the data, writing of the report or in the decision to submit the manuscript for publication.

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Affiliations

  1. Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, 622 West 168th St. PH16-66, New York, NY, 10032, USA

    Joy Vink, Victoria Yu, Sudip Dahal, Conrad Stern-Asher, Mirella Mourad & Ronald J. Wapner

  2. Preterm Birth Prevention Center, Columbia University Irving Medical Center, New York, NY, USA

    Joy Vink & Mirella Mourad

  3. Department of Biological Sciences, Columbia University, New York, NY, USA

    James Lohner & Michael Sheetz

  4. Department of Obstetrics and Gynecology, Rowan University School of Osteopathic Medicine, Camden, NJ, USA

    George Davis

  5. Mailman School of Public Health, Columbia University, New York, NY, USA

    Zenghui Xue & Shuang Wang

  6. Department of Mechanical Engineering, Columbia University, New York, NY, USA

    Kristin Myers

  7. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA

    Jan Kitajewski

  8. Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA

    Xiaowei Chen

  9. Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Epidemiology and Biostatistics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Cande V. Ananth

  10. Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA

    Cande V. Ananth

  11. Environmental and Occupational Health Sciences Institute, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Cande V. Ananth

  12. Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA

    George Gallos

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  1. Joy Vink
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  2. Victoria Yu
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  15. Michael Sheetz
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Contributions

Joy Vink: consented and collected tissue samples, designed and conducted experiments, analyzed the data, and wrote the manuscript. Victoria Yu and Sudip Dahal: conducted the experiments. James Lohner, Michael Sheetz, Kristen Myers, Jan Kitajewski, and Ronald Wapner: assisted with experiment/study design. George Gallos: involved with experiment/study design, analysis/interpretation of data, and writing the manuscript. Mirella Mourad and George Davis: assisted with tissue collection. Zenghui Xue, Shuang Wang, and Cande Ananth performed statistical analyses. Xiaowei Chen: performed pathological analysis of tissue samples. All authors reviewed and edited the manuscript.

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Correspondence to Joy Vink.

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The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board at Columbia University Irving Medical Center (IRBAAAI0337 approved on 12/9/2010; IRBAAAJ2106 approved on 7/25/2012; IRBAAAK3805 approved on 10/24/2012) and at Rowan University School of Osteopathic Medicine (IRB Pro2012002203 approved on 1/17/13).

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Vink, J., Yu, V., Dahal, S. et al. Extracellular Matrix Rigidity Modulates Human Cervical Smooth Muscle Contractility—New Insights into Premature Cervical Failure and Spontaneous Preterm Birth. Reprod. Sci. 28, 237–251 (2021). https://doi.org/10.1007/s43032-020-00268-6

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  • DOI: https://doi.org/10.1007/s43032-020-00268-6

Keywords

  • Cervix
  • Smooth muscle
  • Premature cervical remodeling
  • Pregnancy
  • Extracellular matrix
  • Contractility