REVIEW |
The Role of Sensory Neurons in Cervical Ripening : Effects of Estrogen and Neuropeptides
Department of Neurobiology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio
Correspondence to: Dr. R.E. Papka, Northeastern Ohio Universities College of Medicine, Department of Neurobiology, 4209 State Rt. 44, P.O. Box 95, Rootstown, OH 44272. E-mail: rpapka{at}neoucom.edu
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Summary |
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(J Histochem Cytochem 52:12491258, 2004)
Key Words: cervical ripening sensory nerves substance P calcitonin gene-related peptide vascular endothelial growth factor neuropeptides
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Introduction |
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Until recently, little was known about the action of sensory neurons in parturition or estrogenic effects on peripheral sensory neurons innervating the female reproductive tract, even though a role for sex steroids in the peripheral neurons was proposed over seven decades ago (Nissen 1929). However, two sets of studies helped to direct research in this area. First, the remarkable studies in the early 1970s by Komisaruk et al. (1972)
and Kow and Pfaff (1973)
, which demonstrated enlargement of peripheral sensory fields of genital nerves by 17ß-estradiol in ovariectomized rats. Second, the studies by Carlson and De Feo (1965)
, Higuchi et al. (1987)
, and Burden et al. (1990a)
(b
) showed that pelvic neurectomy (especially the sensory nerve) interfered with parturition. Subsequently, interest in this field has been growing steadily. We now know that estrogen exerts a broad range of biological effects on sensory neurons related to reproductive organs via ERs (Papka et al. 1997
,2000
,2001b
; Papka and Storey-Workley 2002
; Mowa et al. 2003a
,b
).
The "efferent" effects of primary afferent neurons on peripheral target organs is a well-established concept in tissues such as the skin and lungs, but relatively new in the female reproductive organs (reviewed by Holzer 1988; Maggi and Meli, 1988
; also see Collins et al. 2002
and Mowa et al. 2003a
,b
,c
). The present review provides an update on the relationship between estrogen and reproduction-related peripheral sensory neurons of the female, including (1) the distribution pattern of ERs and neuropeptides in reproductive organrelated peripheral sensory neurons during pregnancy and parturition, and (2) the influence of estrogen on neuropeptide synthesis and the effects of neuropeptides on local peripheral tissue changes, in particular the cervical ripening process. These observations point to an interrelationship among (1) the ER and estrogen system, (2) the uterine cervixrelated sensory neurons of the lumbosacral (L6-S1) dorsal root ganglia (DRG), and (3) parturition.
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Estrogen Receptors |
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ERs are members of the steroid/retinoid receptor superfamily that have structural and functional similarities (Mangelsdorf et al. 1995) and are divided into four structurally distinct, functional domains, namely (Figure 1)
: the N-terminal A/B region, which contains the activation function 1 (AF-1) and is responsible for transcriptional activation; the DNA-binding domain, which mediates specific DNA binding and is also called the mid- or C-region; the less-characterized hinge region or D domain; and the C terminus or ligand-binding domain, which contains the ligand-binding pocket and sites for cofactor-binding, transactivation (AF-2), nuclear localization, and interactions with heat shock proteins (for review, see Weihua et al. 2003
). When estrogen binds to its receptors, the ERs dimerize and regulate transcription by binding, in most cases, to the classical consensus estrogen response elements in the promoter region of the target genes, leading to a cellular response (Figure 2) (for review, see Weihua et al. 2003
). ERs also can induce transcription by binding to AP-1 and Sp-1, where ER-
and ER-ß have different and, in some cases, opposing effects (Gaub et al. 1990
; Philips et al. 1993
; Umayahara et al. 1994
; Webb et al. 1995
). Rapid effects of estrogen on neurons are exerted via the recently identified, but less characterized, membrane ER (McEwen 1991
), which may be identified as ER-X (Toran-Allerand et al. 2002
).
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Peripheral Sensory Nerves of the Uterine Cervix |
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Estrogen Receptors in the Sensory Neurons of the Female Reproductive Organs
Distribution
The findings by Komisaruk et al. (1972) and Kow and Pfaff (1973)
that 17ß-estradiol treatment of ovariectomized rats led to the enlargement of the peripheral sensory fields of genital nerves served as the impetus for a series of studies. The initial studies were aimed at characterizing reproductive-related sensory neurons and their expression of ERs using several techniques, including retrograde axonal tracing (Figures 3E and 3F), immunohistochemistry (Figure 3G), in situ hybridization, and RT-PCR (Figures 4 and 5)
(Sohrabji et al. 1994
; Collins et al. 1999
,2002
; Taleghany et al. 1999
; Papka et al. 2000
; Shinohara et al. 2000
; Papka and Storey-Workley 2002
; Mowa et al. 2003a
,b
). Both ER-
and ER-ß mRNA and protein are expressed at significant levels in a subpopulation of small- and medium-sized neurons of lumbosacral (L6-S1) DRG in both postnatal and adult animals, making them important targets of estrogen action (Figure 3G) (Sohrabji et al. 1994
; Papka et al. 1997
,2000
,2001b
; Taleghany et al. 1999
; Shinohara et al. 2000
; Papka and Storey-Workley 2002
).
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Estrogen Modulates Synthesis of Neuropeptides in Sensory Neurons of Female Reproductive Organs |
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Potential Interrelationship among Estrogen, Sensory Neurons, and Cervical Ripening |
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Sensory Neurons and Parturition
The uterus and cervix are richly innervated by fibers of the pelvic nerves (Figures 3A3D). The sensory fiber component of the pelvic nerves is critical for parturition; bilateral dorsal rhizotomy of the L6-S1 roots at days 810 of pregnancy induces dystocia, or difficult birth, whereas bilateral transection of ventral roots does not (Carlson and De Feo 1965; Higuchi et al. 1987
; Burden et al. 1990a
,b
; Martinez-Gomez et al. 1998
). Because the uterus, unlike the cervix, undergoes a physiological loss of innervation over the course of pregnancy (Haase et al. 1997
), it is reasonable to state that the effect of bilateral pelvic neurectomy on parturition, as described above, could be attributed to the disruption of innervation to the cervix. Moreover, preliminary immunohistochemical data from our lab indicate that the neuronal activity of cervix-related sensory neurons increases during pregnancy, as indicated by the increase in expression of phosphorylated cyclic-AMP response element-binding protein immunoreactivity in Fluorogold retrogradely labeled sensory neurons in L6-S1 DRG (Figure 6) (Figures 7A and 7B)
. Interestingly, a trend toward peak activity in cervix-related sensory neurons at day 20 of pregnancy roughly coincides with the onset of cervical ripening at day 19.5.
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Sensory Neuronal Factors Induce Cervical Microvascular Remodeling
The exact mechanism(s) underlying the inflammatory-like effects of SP and CGRP on cervical remodeling are, as yet, unknown. However, the close association of SP and CGRP immunoreactive nerve terminals (Figures 3A3D) and postcapillary venules of the cervix, and the localization of their receptors to the endothelia of these vessels (Collins et al. 2002; Pokabla et al. 2002
) suggest that the SP/CGRP-induced inflammatory-like responses may be mediated by the microvasculature. Indeed, SP administered to virgin rats invokes vasodilation and vascular leakage, leading to leukocyte egress and plasma extravasation in the cervix similar to those seen in parturient rats (Collins et al. 2002
). These changes in the microvasculature may be essential to cervical ripening, in that they may ensure mobilization of leukocytes, the major source of collagenase, and a key catabolic enzyme that dissociates and disorganizes collagen, leading to cervical ripening (Luque et al. 1998
).
Angiogenic Factors in the Ripening Cervix
The angiogenic factor vascular endothelial growth factor (VEGF) has a broad spectrum of vascular effects resembling those that occur in the ripening cervix, such as vascular leakage, vasodilation, and vascular expansion (Bates and Curry 1997; Ferrara and Davis-Smyth 1997
). Therefore, it is possible that VEGF could be one of the modulators of cervical microvascular remodeling in late pregnancy. To date, no study has reported direct or indirect effects of angiogenic factors (in general, and VEGF, in particular) on cervical microvascular remodeling. Nonetheless, Western blot analyses and immunoassays have shown that protein levels of VEGF and its receptors [VEGF R-1 (Flt-1) and VEGF R-2 (KDR)], and activity of VEGF's key intermediate mediators of angiogenesis [phosphorylated antiapoptotic kinase (pAkt) and nitric oxide (NO, measured indirectly as eNOS)], increase remarkably near term in the cervix (Mowa et al., unpublished data). Collectively, these findings imply that some of the microvascular changes associated with cervical ripening are also likely to be induced by VEGF, a potent vasodilator and vascular permeability and inflammation-inducing factor (Bates and Curry 1997
; Ferrara and Davis-Smyth 1997
).
Link between Sensory Neuronal Factors and Angiogenic Factors in the Ripening Cervix
Exactly how endogenous neuropeptides such as SP and CGRP, released from peripheral terminals of sensory nerves, alter the cervical microvasculature remains to be elucidated. However, because levels of both neuropeptides (SP and CGRP) and angiogenic factors (VEGF) rise near term in the cervix (Mowa et al. 2003a,b
,c
; Mowa et al., unpublished data), it is possible that the action of these factors on the cervical microvasculature may be interconnected (Figure 8)
. If such a link does exist, transection of sensory nerves, described above, should alter levels of VEGF. Interestingly, bilateral pelvic neurectomy, which results in loss of sensory neuronal factors such as SP and CGRP, alters concentration of VEGF protein (Mowa et al., unpublished data) (Figure 8). These findings are very important, in that they may help unravel the potential mechanisms likely to mediate the effects of sensory neuronal factors, in general, and SP and CGRP, in particular, during parturition.
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Future Directions and Conclusion |
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Many questions remain unanswered, such as: (1) Are the effects of estrogen on L6-S1 DRG sensory neurons mediated by both membrane and genomic ER? (2) What are the specific neurochemical phenotypes of cervical sensory nerves, and what are their specific patterns of expression during pregnancy, when levels of plasma estrogen are increasing? and (3) Is there a common pathway mediating the effects of VEGF, SP, and/or CGRP and estrogen on cervical microvascular remodeling in the ripening cervix? These and other questions need to be addressed in future research.
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Acknowledgments |
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Footnotes |
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