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Increased Innervation and Ripening of the Prepartum Murine Cervix

Michael A. Kirby, PhD

Jerrick W. Warren

Long T Tran

Departments of Physiology, Pediatrics, and Pathology (division of Anatomy); Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California

Steven M. Yellon, PhD

Departments of Physiology, Pediatrics, and Pathology (division of Anatomy); Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; syellon{at}som.llu.edu

Objective: Ripening of the cervix before birth is coincident with reduced collagen content and leukocyte immigration, characteristics that are analogous to a neurogenic inflammatory-like process. We sought to assess the morphologic relationship between innervation and remodeling of the peripatum cervix.

Methods: Cervix was obtained from C3H/HeN mice on days 15 and 18 of pregnancy, 1 day postpartum, and from non-pregnant controls. Tissues were immersion-fixed, paraffin-embedded, and some sections stained with Picrosirius red to assess collagen content and complexity of organization. By image analysis of optical density, collagen content and structure were significantly decreased by the day before birth. Other sections were processed to visualize nerve fibers by immunohistochemistry with antibodies against neuron-specific epitopes, PGP9.5, peripherin, as well as brain nitric oxide synthase (bNOS), calcitonin gene-related peptide (CGRP), and other neuropeptides. Fiber density was assessed stereologically and normalized to cell density in non-pregnant cervix to correct for tissue hypertrophy due to reproductive status.

Results: In groups of non-pregnant, day 15 pregnant, and postpartum mice, cervix contained nerve fibers tghat were immunoreactive for the pan-neural markers PGP9.5 and peripherin. Punctate and beaded varicosities were sparsely distributed in stroma, subepithelium, and in proximity to vascular structures. By day 18 of pregnancy, 1 day before birth, fiber density was increased fourfold or more compared to other groups. bNOS fiberrs and, to a lesser extent, CGRP accounted for most of the increased innervation of the murine cervix by the day before birth, a period when macrophage numbers are enhanced.

Conclusions: The findings suggest that increased bNOS and CGRP innervation contribute to early inflammatory-like processes that ripen the cervix before birth.

Key Words: Leukocyte • neuropeptides • bNOS • parturition

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