Structural, functional and molecular pathogenesis of pelvic organ prolapse in patient and Loxl1 deficient mice

Yu Li,Xiaohui Zou,Fangyuan Bao,Chengrui An,Lin Gong,Hongxia Cai,Xudong Yao,Nanfang Nie,Bingbing Wu,Yanshan Liu,Chunbo Yang

doi:10.18632/aging.203777

Abstract

Pelvic organ prolapse is a worldwide health problem to elderly women. Understanding its pathogenesis and an ideal animal model are crucial to developing promising treatments. The present study aimed to investigate new clinical significance and detailed mechanism of pelvic organ prolapse by comparing the structural, functional and molecular dysfunctions of pelvic organ prolapse in patient and Loxl1 deficient mice. Our results showed that human vagina tissues from prolapsed site showed disarranged collagen and elastic fibers compared with the non-prolapse tissue. A gene ontology (GO) analysis of differentially expressed genes revealed molecular changes mainly related to inflammatory response and extracellular matrix (ECM) organization. While the mice lacking Loxl1 developed stable POP phenotype and disordered ECM structure in histology. Such Loxl1 knockout mice exhibited a significantly urinary dysfunction and decreased mechanical properties of the pelvic floor tissues, implying that POP in human condition might be induced by progressively decreased mechanics of pelvic tissues following ECM catabolism. Similarly, we not only identified significant up-regulated ECM catabolism processes and down-regulated ECM synthesis processes, but also characterized high level of inflammatory response in vagina tissue of the Loxl1 deficient mice. Thus, all these pathological changes in the POP mice model was consistent with those of the clinical elderly patients. These findings provide new insight into remodeling of POP by LOXL1 regulation and be of great importance to develop combination treatments of ECM metabolism and inflammation regulation strategy.

Highlights

Pelvic organ prolapse [1] refers to the pelvic floor support functional disorder with the female pelvic cavity visceramoving down along their normal position
Lysyl oxidase like-1 (Loxl1) is a key enzyme in maintaining the dynamic homeostasis of elastin fibers [13]
The Inter-Quartile Range (IQR) of the average leak point pressure (LPP)-peak value could represent the functional stability of bladder under pressure. These results demonstrated that loxl1 deficiency was associated with the reduction in mechanical property of pelvic floor and urinary function

Summary

Introduction

Pelvic organ prolapse [1] refers to the pelvic floor support functional disorder with the female pelvic cavity viscera (such as bladder, uterus, vaginal stump, etc.)moving down along their normal position. Several animal species, including non-human primates (NHPs, such as rhesus monkeys, squirrel monkeys, baboons), pigs, cattle and sheep have been studied to spontaneously mimic forms of POP in women [4]. These big animals are not conducive for use in laboratory research due to long production period and high cost [5,6,7,8]. The validation of Loxl knockout mice acting as POP model mainly include that the anatomical and functional phenotype resemble POP in human. Whether Loxl knockout mice can match the pathology of POP in human remains unclear, and the correlation between human and mice model still warrants further investigation

Methods

Results

Discussion

Conclusion