Single-cell and spatial multi-omics reveal estrogen-mediated vaginal wall microenvironment remodeling and a perivascular reparative niche in postmenopausal pelvic organ prolapse.

Introduction: Local estrogen is widely used to improve vaginal mucosal status and relieve menopausal urogenital symptoms in patients with pelvic organ prolapse (POP), yet clinical outcomes are inconsistent. This creates an urgent need to clarify the tissue-specific mechanisms of estrogen action. Methods: In this study, we combined single-cell RNA sequencing and high-resolution Visium HD spatial transcriptomics to profile postmenopausal vaginal wall tissues at near-cellular resolution. Computational pharmacology analysis was also performed to predict distinct responses of this tissue niche to different estrogen subtypes. Results: We found estrogen drives selective expansion and spatial redistribution of HAS1+ fibroblasts, which aggregate with pericytes to form a structured perivascular niche. Such spatial co-localization strengthens fibroblast-pericyte crosstalk and activates multiple pro-repair signaling cascades. Discussion: Our results demonstrate that estrogen functions by forming spatially organized multicellular reparative niches rather than non-selective tissue activation. This work provides a theoretical basis for developing targeted POP therapies, while further experimental verification is still needed.