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

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.