Transection of the Pelvic or Vagus Nerve Forestalls Ripening of the Cervix and Delays Birth in Rats1

Abstract

Innervation of the cervix is important for normal timing of birth because transection of the pelvic nerve forestalls birth and causes dystocia. To discover whether transection of the parasympathetic innervation of the cervix affects cervical ripening in the process of parturition was the objective of the present study. Rats on Day 16 of pregnancy had the pelvic nerve (PnX) or the vagus nerve (VnX) or both pathways (PnX+VnX) transected, sham-operated (Sham) or nonpregnant rats served as controls. Sections of fixed peripartum cervix were stained for collagen or processed by immunohistochemistry to identify macrophages and nerve fibers. All Sham controls delivered by the morning of Day 22 postbreeding, while births were delayed in more than 75% of neurectomized rats by more than 12 h. Dystocia was evident in more than 25% of the PnX and PnX+VnX rats. Moreover, on prepartum Day 21, serum progesterone was increased severalfold in neurectomized versus Sham rats. Assessments of cell nuclei counts indicated that the cervix of neurectomized rats and Sham controls had become equally hypertrophied compared to the unripe cervix in nonpregnant rats. Collagen content and structure were reduced in the cervix of all pregnant rats, whether neurectomized or Shams, versus that in nonpregnant rats. Stereological analysis of cervix sections found reduced numbers of resident macrophages in prepartum PnX and PnX+VnX rats on Day 21 postbreeding, as well as in VnX rats on Day 22 postbreeding compared to that in Sham controls. Finally, nerve transections blocked the prepartum increase in innervation that occurred in Sham rats on Day 21 postbreeding. These findings indicate that parasympathetic innervation of the cervix mediates local inflammatory processes, withdrawal of progesterone in circulation, and the normal timing of birth. Therefore, pelvic and vagal nerves regulate macrophage immigration and nerve fiber density but may not be involved in final remodeling of the extracellular matrix in the prepartum cervix. These findings support the contention that immigration of immune cells and enhanced innervation are involved in processes that remodel the cervix and time parturition.

Loss of Progesterone Receptor-Mediated Actions Induce Preterm Cellular and Structural Remodeling of the Cervix and Premature Birth

“…Evidence that PR antagonists act on negative feedback centers in the brain [46], [47] contributes to the novel consideration that parasympathetic-mediated central innervation [6], in addition to local progesterone actions, may recruit macrophages and promote inflammatory processes that remodel the cervix prior to birth at term. Whether specific parasympathetic neuromediators affect characteristics associated with cervical remodeling remains to be determined.…”

“…At term across a variety of mammalian species, structural changes that resemble an inflammatory process occur in the cervix well before onset of active labor [1]–[4]. Findings in the prepartum cervix of several strains and species of rodents at term indicate reduced density of cells in the subepithelium and stroma, degradation of extracellular collagen matrix, and increased numbers of macrophages/area relative to earlier pregnancy or in nonpregnant controls [3]–[6]. More macrophages in the prepartum cervix of mice were recently confirmed by flow cytometry [6].…”

“…Findings in the prepartum cervix of several strains and species of rodents at term indicate reduced density of cells in the subepithelium and stroma, degradation of extracellular collagen matrix, and increased numbers of macrophages/area relative to earlier pregnancy or in nonpregnant controls [3]–[6]. More macrophages in the prepartum cervix of mice were recently confirmed by flow cytometry [6]. These characteristics associated with cervical remodeling occur near the peak of serum progesterone concentrations, 2–4 days before the onset of labor at term in rodents [7]–[10].…”

Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform

“…As term approaches, remodeling of the cervix is characterized by reduced density of cell nuclei, degradation of extracellular matrix collagen content and structure, and immigration of immune cells [17][18][19][20]. By the day before birth, immune cells have immigrated into the stroma and perimetrium of the cervix in mice [21,22] and rats [23,24]. Evidence in primates also suggests that these characteristics of inflammation are part of the process that remodels the cervix [25][26][27].…”

Estrogen and female reproductive tract innervation: Cellular and molecular mechanisms of autonomic neuroplasticity

“…Transection of the sensory branch of the rat pelvic nerve delays labor (Mackay et al, 2009), while transection of sympathetic hypogastric nerves has no effect on cervical ripening or birth (Kirby et al, 2005; Boyd et al, 2009). Transection of parasympathetic pathways (pelvic and vagus nerves) delays birth, affects local inflammatory processes including macrophage immigration, and prevents the normal withdrawal of progesterone from circulation (Clyde et al, 2011). In contrast, pelvic and vagal parasympathetic neurectomy is not involved in the final remodeling of the cervix at term.…”