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Innervation of ectopic endometrium in a rat model of endometriosis

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Berkley, Karen J., Dmitrieva, Natalia, Curtis, Kathleen S., Papka, Raymond E.·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0403663101PMC PMC491992
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Abstract

Endometriosis (ENDO) is a disorder in which vascularized growths of endometrial tissue occur outside the uterus. Its symptoms include reduced fertility and severe pelvic pain. Mechanisms that maintain the ectopic growths and evoke symptoms are poorly understood. One factor not yet considered is that the ectopic growths develop their own innervation. Here, we tested the hypothesis that the growths develop both an autonomic and a sensory innervation. We used a rat model of surgically induced ENDO whose growths mimic those in women. Furthermore, similar to women with ENDO, such rats exhibit reduced fertility and increased pelvic nociception. The ENDO was induced by autotransplanting, on mesenteric cascade arteries, small pieces of uterus that formed vascularized cysts. The cysts and healthy uterus were harvested from proestrous rats and immunostained using the pan-neuronal marker PGP9.5 and specific markers for calcitonin gene-related peptide (CGRP) (sensory C and Aδ fibers), substance P (SP) (sensory C and Aδ fibers) and vesicular monoamine transporter (sympathetic fibers). Cysts (like the uterus) were robustly innervated, with many PGP9.5-stained neurites accompanying blood vessels and extending into nearby luminal epithelial layers. CGRP-, SP-, and vesicular monoamine transporter-immunostained neurites also were observed, with CGRP and SP neurites extending the furthest into the cyst lining. These results demonstrate that ectopic endometrial growths develop an autonomic and sensory innervation. This innervation could contribute not only to symptoms associated with ENDO but also to maintenance of the ectopic growths.

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  • Sensory fibers whose branches innervate ectopic growths immunostain with antibodies to calcitonin gene-related peptide, indicating that CGRP-positive fibers include C-fiber nociceptors.

    “Sensory fibers whose branches innervate ectopic growths immunostain with antibodies to calcitonin gene-related peptide (CGRP) (Berkley et al., 2004(Berkley et al., , 2005)), indicating that the CGRP-positive fibers include C-fiber nociceptors (Snider and McMahon, 1998).”

    From Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications (2011) · cites this paper as Berkley et al., 2004

  • Sensory and sympathetic fibers directly innervate ectopic endometrial growths in a rat model and in lesions from women.

    “Direct innervation of ectopic endometrial growths by sensory and sympathetic fibers was shown in endometriosis growths from a rat model (Berkley et al., 2004) and lesions from women (Berkley et al., 2005).”

    From Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications (2011) · cites this paper as Berkley et al., 2004

  • Immunohistochemical detection of PGP9.5, a highly specific pan-neuronal marker, was described at peritoneal lesions developing from surgically transplanted uterine horn segments in a rat model of endometriosis.

    “Immunohistochemical detection of the protein gene product 9.5 (PGP9.5), a highly specific pan-neuronal marker, was described at peritoneal lesions developing from surgically transplanted uterine horn segments in a rat model of endometriosis [138].”

    From Update on biomarkers for the detection of endometriosis (2015) · cites this paper as [138]

  • Fiber characteristics at six weeks post-transplant were virtually identical to those previously observed in established cysts.

    “Overall, fiber characteristics at six weeks post-transplant were virtually identical to those previously observed in established cysts [10].”

    From Sprouted Innervation into Uterine Transplants Contributes to the Development of Hyperalgesia in a Rat Model of Endometriosis (2012) · cites this paper as [10]

  • Ectopic growths from ENDO rats and women with established endometriosis develop their own C-fiber (sensory afferent) and sympathetic nerve supply.

    “Our group discovered that ectopic growths harvested from ENDO rats and women with established endometriosis develop their own C-fiber (sensory afferent) and sympathetic (autonomic efferent) nerve supply.”

    From Sprouted Innervation into Uterine Transplants Contributes to the Development of Hyperalgesia in a Rat Model of Endometriosis (2012) · cites this paper as [10]

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Authors
Berkley, K. J., Dmitrieva, N., Curtis, K. S., & Papka, R. E.
Affiliations
Florida State University (US)
ORCID
Dmitrieva, Natalia
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-07-15
Volume
101
Issue
30
Pages
11094-11098
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0403663101
PMC
PMC491992
OpenAlex
W2084180916
Cited by
227
References
53
Citations by year
2026: 3 · 2025: 7 · 2024: 11 · 2023: 5 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 13 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 13 · 2014: 15 · 2013: 12 · 2012: 10
FWCI
9.09
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01-NS-11892, R01 NS22526, R01NS022526, R01NS011892)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
Keywords
endometriosis, ectopic endometrium, nerve innervation, sensory innervation, autonomic innervation, calcitonin gene-related peptide, substance P, vesicular monoamine transporter, PGP 9.5, pelvic pain, fertility, surgically induced endometriosis, rat model, endometrial cysts
MeSH terms
Animals, Disease Models, Animal, Endometriosis, Endometrium, Female, Immunohistochemistry, Infertility, Female, Nerve Tissue Proteins, Biomarkers, Neurites, Rats, Sprague-Dawley, Rats

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