title: A new paradigm for the role of smooth muscle cells in the human cervix.
abstract: Premature cervical remodeling resulting in spontaneous preterm birth may begin with premature failure or relaxation at the internal os (termed "funneling"). To date, we do not understand why the internal os fails or why funneling occurs in some cases of premature cervical remodeling. Although the human cervix is thought to be mostly collagen with minimal cellular content, cervical smooth muscle cells are present in the cervix and can cause cervical tissue contractility.
  
  
  
  To understand why the internal os relaxes or why funneling occurs in some cases of premature cervical remodeling, we sought to evaluate cervical smooth muscle cell content and distribution throughout human cervix and correlate if cervical smooth muscle organization influences regional cervical tissue contractility.
  
  
  
  Using institutional review board-approved protocols, nonpregnant women <50 years old undergoing hysterectomy for benign indications were consented. Cervical tissue from the internal and external os were immunostained for smooth muscle cell markers (α-smooth muscle actin, smooth muscle protein 22 calponin) and contraction-associated proteins (connexin 43, cyclooxygenase-2, oxytocin receptor). To evaluate cervical smooth muscle cell morphology throughout the entire cervix, whole cervical slices were obtained from the internal os, midcervix, and external os and immunostained with smooth muscle actin. To correlate tissue structure with function, whole slices from the internal and external os were stimulated to contract with 1 μmol/L of oxytocin in organ baths. In separate samples, we tested if the cervix responds to a common tocolytic, nifedipine. Cervical slices from the internal os were treated with oxytocin alone or oxytocin + increasing doses of nifedipine to generate a dose response and half maximal inhibitory concentration. Student t test was used where appropriate.
  
  
  
  Cervical tissue was collected from 41 women. Immunohistochemistry showed cervical smooth muscle cells at the internal and external os expressed mature smooth muscle cell markers and contraction-associated proteins. The cervix exhibited a gradient of cervical smooth muscle cells. The area of the internal os contained 50-60% cervical smooth muscle cells that were circumferentially organized in the periphery of the stroma, which may resemble a sphincter-like pattern. The external os contained approximately 10% cervical smooth muscle cells that were randomly scattered in the tissue. In organ bath studies, oxytocin stimulated the internal os to contract with more than double the force of the external os (1341 ± 693 vs 523 ± 536 integrated grams × seconds, respectively, P = .009). Nifedipine significantly decreased cervical tissue muscle force compared to timed vehicle control (oxytocin alone) at doses of 10(-5) mol/L (vehicle 47% ± 15% vs oxytocin + nifedipine 24% ± 16%, P = .007), 10(-4) mol/L (vehicle 46% ± 16% vs oxytocin + nifedipine -4% ± 20%, P = .003), and 10(-3) mol/L (vehicle 42% ± 14% vs oxytocin + nifedipine -15% ± 18%, P = .0006). The half maximal inhibitory concentration for nifedipine was 1.35 × 10(-5) mol/L.
  
  
  
  Our findings suggest a new paradigm for cervical tissue morphology-one that includes the possibility of a specialized sphincter at the internal os. This new paradigm introduces novel avenues to further investigate potential mechanisms of normal and premature cervical remodeling.
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY. Electronic address: jyv2101@cumc.columbia.edu.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Vink
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
authors.forename: Sisi
authors.initials: S
authors.lastname: Qin
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
authors.forename: Clifton O
authors.initials: CO
authors.lastname: Brock
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
authors.forename: Noelia M
authors.initials: NM
authors.lastname: Zork
authors.affiliation: Department of Maternal-Fetal Medicine, Intermountain Healthcare, Provo, UT; Medical Physics Department, University of Wisconsin, Madison, WI.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Feltovich
authors.affiliation: Department of Pathology, Columbia University Medical Center, New York, NY.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Intermountain Healthcare, Provo, UT.
authors.forename: Paul
authors.initials: P
authors.lastname: Urie
authors.affiliation: Department of Mechanical Engineering, Columbia University, New York, NY.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Myers
authors.affiliation: Medical Physics Department, University of Wisconsin, Madison, WI.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hall
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wapner
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Kitajewski
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Shawber
authors.affiliation: Department of Anesthesia, Columbia University Medical Center, New York, NY.
authors.forename: George
authors.initials: G
authors.lastname: Gallos
mesh_terms: D000328:Adult; D002584:Cervix Uteri / Q000166:cytology* / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010120:Oxytocics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D047928:Premature Birth / Q000209:etiology / Q000503:physiopathology; D015149:Tocolytic Agents / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D010120:Oxytocics; D015149:Tocolytic Agents; D010121:Oxytocin; D009543:Nifedipine
keywords: cervix; premature cervical remodeling; smooth muscle cells