Nociceptive Nerve-Derived CGRP Exacerbates Uterine Fibrogenesis in Adenomyosis by Promoting CD140b+ CD146+ Fibroblast Differentiation

  • Adv Sci (Weinh). 2025 Sep 23:e07128. doi: 10.1002/advs.202507128.
Zi Ye  1  2  3  4 ,  Anning Zhao  1  2  3 ,  Xia Li  1  2  3 ,  Yanqing Hao  3 ,  Dong Huang  1  2  3 ,  Jianmin Chen  1  2  3 ,  Tiantian Li  1  2  3 ,  Yangyang Dai  1  2  3 ,  Wenchao Sun  5 ,  Lie Ma  3  4 ,  Songying Zhang  1  2  3 ,  Liaobing Xin  1  2  3
Affiliations
  • 1. Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
  • 2. Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou, 310016, China.
  • 3. Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, 310016, China.
  • 4. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China.
  • 5. Department of Reproductive Endocrinology, Hangzhou Women's Hospital, Hangzhou, 310008, China.
PMID: 40985151 DOI: 10.1002/advs.202507128
Abstract

Progressive dysmenorrhea and extensive fibrosis within the myometrium are hallmark features of adenomyosis (AM). Approximately 80% of patients with AM experience secondary dysmenorrhea, which occurs more frequently in AM than in Other gynecological disorders. Because nociceptive nerves mediate dysmenorrhea, their contribution to AM-associated fibrosis is investigated. These results demonstrate overexpression of Calcitonin gene-related peptide (CGRP)+ nociceptive nerves within fibrotic lesions in both AM patients and murine models; nociceptive nerve ablation reduces uterine fibrosis in mice with induced AM. CGRP, secreted by nociceptive nerves, drives receptor activity-modifying protein 1 (RAMP1) high-expressing (RAMP1hi) CD140b+ CD146+ fibroblasts in AM lesions toward an extracellular matrix deposition subtype through activation of the extracellular signal-regulated kinase pathway. Treatment of mice with AM using rimegepant, a United States Food and Drug Administration-approved drug that blocks CGRP/RAMP1 signaling, alleviated progression of AM-associated fibrosis and promoted fertility restoration. This study identifies a previously unrecognized nerve-fibroblast crosstalk mechanism and provides a potential nonhormonal therapeutic strategy for AM treatment, particularly in women of reproductive age.

Keywords
CD140b+ CD146+ fibroblasts; CGRP; adenomyosis; fibrogenesis; nociceptive nerve.
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