Localization of Catecholaminergic Neurofibers in Pregnant Cervix as a Possible Myometrial Pacemaker

Abstract

In eutocic labor, the autonomic nervous system is dominated by the parasympathetic system, which ensures optimal blood flow to the uterus and placenta. This study is focused on the detection of the quantitative presence of catecholamine (C) neurofibers in the internal uterine orifice (IUO) and in the lower uterine segment (LUS) of the pregnant uterus, which could play a role in labor and delivery. A total of 102 women were enrolled before their submission to a scheduled cesarean section (CS); patients showed a singleton fetus in a cephalic presentation outside labor. During CS, surgeons sampled two serial consecutive full-thickness sections 5 mm in depth (including the myometrial layer) on the LUS and two randomly selected samples of 5 mm depth from the IUO of the cervix. All histological samples were studied to quantify the distribution of A nerve fibers. The authors demonstrated a significant and notably higher concentration of A fibers in the IUO (46 ± 4.8) than in the LUS (21 ± 2.6), showing that the pregnant cervix has a greater concentration of A neurofibers than the at-term LUS. Pregnant women's mechanosensitive pacemakers can operate normally when the body is in a physiological state, which permits normal uterine contractions and eutocic delivery. The increased frequency of C neurofibers in the cervix may influence the smooth muscle cell bundles' activation, which could cause an aberrant mechano-sensitive pacemaker activation-deactivation cycle. Stressful circumstances (anxiety, tension, fetal head position) cause the sympathetic nervous system to become more active, working through these nerve fibers in the gravid cervix. They might interfere with the mechano-sensitive pacemakers, slowing down the uterine contractions and cervix ripening, which could result in dystocic labor.

Keywords: catecholamine; cervix; cesarean section; delivery; labor; lower uterine segment (LUS); neurotransmitters; pregnancy; uterine pacemaker.

Figure 1

Sagittal section of the human pregnant cervix and LUS in early labor. In the red box is the smooth muscle bundle from the pregnant cervix and LUS, both regulated by adrenergic neurofibers (the yellow cell). The blue cell is the Cajal-like cell, which mediates, amplifies, and regulates bioelectrical signaling between the sensitive motor neurofibers and the smooth uterine cells through the gap junction.

Figure 2

Drawing of pregnant LUS and a cervix out of labor with a fetal cephalic presentation. The red circle shows the LUS site where a biopsy was performed during the elective CS, whereas the blue circle indicates the site of the cervix of the anatomic internal uterine orifice.

Figure 3

Interaction between the ICC and A neurofibers in the uterine cervix. (a) drawing of the cervix of an at-term uterus out of labor; (b) section of the muscular layer of the gravid cervix composed of smooth muscle cells (in red), Cajal-like cells/interstitial Cajal cells (ICC) (in blue), catecholamine neurofibers with varicosities (in yellow) and gap junction (in green); (c) an A neurofiber with a series of vesicles containing catecholamine molecules (red spheres) are released; (d) the release of adrenaline from the sympathetic terminals determines the activation of α1 adrenergic receptor at the level of the ICC. The activation of this receptor determines the depolarization of the membrane potential in ICC, following the activation of inward ionic current, which is transmitted through the gap junction to the syncytial smooth muscle cells. The depolarization of the smooth muscle cells determines the influx of calcium ions through the voltage-gated calcium channels and the development of the contraction process.

Figure 4

Possible localization of uterine pacemakers in a pregnant uterus in labor. The blue dots are the mechano-sensitive pacemakers innervated by sympathetic neurofibers and activated by changes in intrauterine pressure. The blue arrows represent the amplification of the regional action potential by bioelectrical propagation. The more the intrauterine pressure (IUP) increases, the more mechanosensitive pacemakers (blue dots) are recruited, as shown in the right blue and yellow graphic. The yellow ellipses are active pacemakers. The red star represents the active leading pacemaker.

Figure 5

Proposed mechanism of pacemaker activation. Fetal head compression on the gravid cervix and IUO stimulates autonomous nerve fibers; at this point, there are two possible pathways: The green one represents the physiological pathway in which there is a dominance of the parasympathetic nervous system coupled with normal oxytocin activity, leading to normal stimulation and activity of cervical pacemakers and thus cervical ripening, dilatation, and eutocic delivery. The red one represents a pathologic pathway in which there is abnormal activation of the sympathetic nervous system because of external or internal stress stimuli (anxiety, fetal head malposition), leading to a tocolytic effect of catecholamines and abnormal cervical pacemaker stimulation and activity, causing alterations in cervical ripening and dilatation and, thus, dystocic labor.

Figure 6

Sites of the biopsies performed during the elective cesarean section on the LUS and the gravid cervix. On the top right, a clock-like view from the top of the gravid cervix shows the cervix divided into 4 quarters A, B, C, and D. During the ECS, two samples were obtained from two random spots in these 4 quarters. The green box shows a TUS longitudinal scan of the gravid cervix; in this way, US was used to detect the IUO where the biopsies were obtained.