Abstract
The changes in the mechanical integrity of the cervix during pregnancy have implications for a successful delivery. Cervical collagens are known to remodel extensively in mice with progressing gestation leading to a soft cervix at term. During this process, mature crosslinked collagens are hypothesized to be replaced with immature less crosslinked collagens to facilitate cervical softening and ripening. To determine the mechanical role of collagen crosslinks during normal mouse cervical remodeling, tensile load-to-break tests were conducted for the following time points: nonpregnant (NP), gestation day (d) 6, 12, 15, 18 and 24 hr postpartum (PP) of the 19-day gestation period. Immature crosslinks (HLNL and DHLNL) and mature crosslinks (DPD and PYD) were measured using ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS). There were no significant changes in the total immature crosslink density (HLNL+DHLNL mol per collagen mol) throughout normal mouse gestation (range: 0.31–0.49). Total mature crosslink density (PYD+DPD mol per collagen mol) decreased significantly in early softening from d6 to d15 (d6: 0.17, d12: 0.097, d15: 0.026) and did not decrease with further gestation. The maturity ratio (total mature to total immature crosslinks) significantly decreased in early softening from d6 to d15 (d6: 0.2, d15: 0.074). All of the measured crosslinks correlated significantly with a measure of tissue stiffness and strength, with the exception of the immature crosslink HLNL. This data provides quantitative evidence to support the hypothesis that as mature crosslinked collagens decline, they are replaced by immature collagens to facilitate increased tissue compliance in the early softening period from d6 to d15.
Highlights
During pregnancy, the cervix is the mechanical barrier that must remain closed until term, and must dramatically remodel into a compliant structure to allow for a successful term delivery
We have previously shown that PYD values remain elevated in a mouse model with a parturition defect due to disrupted cervical remodeling [11], and we have shown that DHLNL, PYD, and DPD crosslinks exist in nonpregnant human cervical tissue [12]
Total immature crosslink density (HLNL+DHLNL) increased from NP to d6, but not significantly (NP: 0.31 to d6: 0.51) and they decreased between d12 and d15, but not significantly (d12: 0.59 vs d15: 0.36)
Summary
The cervix is the mechanical barrier that must remain closed until term, and must dramatically remodel into a compliant structure to allow for a successful term delivery. We seek to understand the changes in collagen crosslinks with progressing gestation and how they relate to tensile mechanical properties of the cervix. The objectives of this study are: to identify and quantify the types of collagen crosslinks in the cervix and to determine the correlation between crosslinks and tensile mechanical properties of the tissue over the course of mouse pregnancy. We hypothesize that mature collagen crosslinks will decrease as mature collagen fibers are broken down in normal gestation to facilitate cervical remodeling. We hypothesize that new collagens are synthesized during normal remodeling and the level of immature collagen crosslinks will increase in early pregnancy [2,3]. We hypothesize that samples with increased crosslink density, especially mature trivalent crosslinks, will have higher mechanical stiffness and strength [4,5]
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