Therapeutic Effects of 17β-Estradiol on Pelvic Organ Prolapse by Inhibiting Mfn2 Expression: An In Vitro Study

Wang, Xiaoqing; He, Rui-Ju; Xiao, Bingbing; Lu, Ye

doi:10.3389/fendo.2020.586242

Cited by 12 publications

(9 citation statements)

References 37 publications

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“…This may imply that the vaginal fibroblasts were stimulated to synthesize factors involved in ECM deposition and remodeling at 2% E2 concentration. It was found previously that fibroblast activity may be promoted at a certain level of exposure to E2 rather than showing a linearly increasing dose response . Even though the addition of E2 to electrospun P4HB scaffolds had not been reflected in enhanced cellular functions at the protein level, gene-level data could possibly mean in vivo enhanced tissue regeneration, healing, and increased mechanical strength with certain E2 concentrations.…”

Section: Discussionmentioning

confidence: 89%

“…It was found previously that fibroblast activity may be promoted at a certain level of exposure to E2 rather than showing a linearly increasing dose response. 48 Even though the addition of E2 to electrospun P4HB scaffolds had not been reflected in enhanced cellular functions at the protein level, gene-level data could possibly mean in vivo enhanced tissue regeneration, healing, and increased mechanical strength with certain E2 concentrations. In vitro , E2 incorporation in other electrospun scaffolds has demonstrated to increase collagen and elastin production.…”

Section: Discussionmentioning

confidence: 99%

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Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery

Verhorstert

Gudde

Weitsz

et al. 2022

ACS Appl. Bio Mater.

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Women with pelvic organ prolapse (POP) have bothersome complaints that significantly affect their quality of life. While native tissue repair is associated with high recurrence rates, polypropylene knitted implants have caused specific implant-related adverse events that have detrimental, often irreversible, effects. We hypothesize that surgical outcome can be improved with a tissue-engineered solution using an absorbable implant that mimics the natural extracellular matrix (ECM) structure, releases estrogen, and activates collagen metabolism by fibroblasts as the main regulators of wound healing. To this aim, we produced electrospun poly-4-hydroxybutyrate (P4HB) scaffolds and biofunctionalized them with estradiol (E2). The cell–implant interactions relevant for POP repair were assessed by seeding primary POP vaginal fibroblasts isolated from patients on electrospun P4HB scaffolds with 1%, 2%, or 5% E2 and without E2. To test our hypothesis on whether ECM mimicking structures should improve regeneration, electrospun P4HB was compared to knitted P4HB implants. We evaluated vaginal fibroblast proliferation, ECM deposition, and metabolism by quantification of collagen, elastin, and matrix metalloproteinases and by gene expression analysis for 28 days. We established effective E2 drug loading with a steady release over time. Significantly higher cell proliferation, collagen-, and elastin deposition were observed on electrospun P4HB scaffolds as compared to knitted P4HB. For this study, physical properties of the scaffolds were more determinant on the cell response than the release of E2. These results indicate that making these electrospun P4HB scaffolds E2-releasing appears to be technically feasible. In addition, electrospun P4HB scaffolds promote the cellular response of vaginal fibroblasts and further studies are merited to assess if their use results in improved surgical outcomes in case of POP repair.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery

Verhorstert

Gudde

Weitsz

et al. 2022

ACS Appl. Bio Mater.

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“…In a recent study in pigs, increased abundance of estrogen precursors (androstenedione and androsterone) and other forms of estrogen (estrone and 17β-estradiol) were reported in sows with high versus low POP risk ( Kiefer et al, 2021a ). Moreover, several studies in humans have suggested changes in ESR1 gene expression levels to be associated with POP risk ( Zbucka-Kretowska et al, 2011 ; Wang et al, 2020 ), as it plays a supportive role in controlling the synthesis and breakdown of collagen in the pelvic region ( Robinson and Cardozo, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of the genetic basis of sow pelvic organ prolapse

et al. 2023

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Introduction: Pelvic organ prolapse (POP) is one contributor to recent increases in sow mortality that have been observed in some populations and environments, leading to financial losses and welfare concerns.Methods: With inconsistent previous reports, the objective here was to investigate the role of genetics on susceptibility to POP, using data on 30,429 purebred sows, of which 14,186 were genotyped (25K), collected from 2012 to 2022 in two US multiplier farms with a high POP incidence of 7.1% among culled and dead sows and ranging from 2% to 4% of all sows present by parity. Given the low incidence of POP for parities 1 and >6, only data from parities 2 to 6 were retained for analyses. Genetic analyses were conducted both across parities, using cull data (culled for POP versus another reason), and by parity, using farrowing data. (culled for POP versus culled for another reason or not culled).Results and Discussion: Estimates of heritability from univariate logit models on the underlying scale were 0.35 ± 0.02 for the across-parity analysis and ranged from 0.41 ± 0.03 in parity 2 to 0.15 ± 0.07 in parity 6 for the by-parity analyses. Estimates of genetic correlations of POP between parities based on bivariate linear models indicated a similar genetic basis of POP across parities but less similar with increasing distance between parities. Genome wide association analyses revealed six 1 Mb windows that explained more than 1% of the genetic variance in the across-parity data. Most regions were confirmed in several by-parity analyses. Functional analyses of the identified genomic regions showed a potential role of several genes on chromosomes 1, 3, 7, 10, 12, and 14 in susceptibility to POP, including the Estrogen Receptor gene. Gene set enrichment analyses showed that genomic regions that explained more variation for POP were enriched for several terms from custom transcriptome and gene ontology libraries.Conclusion: The influence of genetics on susceptibility to POP in this population and environment was confirmed and several candidate genes and biological processes were identified that can be targeted to better understand and mitigate the incidence of POP.

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“…Our finding suggested that estrogen defends the muscles and fascia of the pelvic floor against the damage caused by mechanical strain such as vaginal delivery, but the protective effect diminished in postmenopausal women due to the rapid reduction of estrogen levels, which to some extent explains why POP mainly occurs after menopause. Recently, estrogen was proved to restrain the progress of POP by inhibiting the expression level of Mitofusin-2 and promoting expression of procollagens and proliferation of fibroblasts ( Wang et al, 2020 ). Moreover, estrogen is known to have a positive effect on epithelial thickness and blood flow ( Trutnovsky, 2021 ), and therefore is well accepted for prolapse-associated complications therapy.…”

Section: Discussionmentioning

confidence: 99%

The protective effect of 17 β-estradiol on human uterosacral ligament fibroblasts from postmenopausal women with pelvic organ prolapse

Xie

Guo

et al. 2022

Front. Physiol.

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This study aims to explore the protective effects of 17 β-estradiol on the human uterosacral ligament fibroblasts (hUSLFs) under static or stretched conditions. The experiments were performed on hUSLFs derived from pelvic organ prolapse (POP) and non-POP patients. Fibroblasts were cultured after collagenase digestion and identified by morphological observation and immunocytochemical methods. 17 β-estradiol (10−10 M and 10−9 M) and mechanical stress induced by the FX-5000 T-cell stress loading system under a loading strain of 1/2 sin waveform uniaxial cyclic stress with a tensile strain of 20% and a frequency of 0.5 Hz were either or both applied on hUSLFs. Cell proliferation was measured by CCK8, and cell apoptosis and death were detected using Annexin V/7-AAD staining and flow cytometric analysis. We found that the fibroblasts growth rate of POP patients was significantly lower than controls. The cell apoptosis and death rate increased as the mechanical load intensifying. After 20% mechanical stretching for 24 h, the dead cell rate was higher in POP than control. Notably, 17 β-estradiol treatment reversed mechanical stress induced hUSLFs apoptosis and death in both POP and Control cells. The protein and mRNA levels of anti-apoptotic PARP1 (poly-ADP-ribose polymerase) and Bcl-2 were increased by estrogen treatment. Meanwhile, expression of estrogen receptor α, a target of Poly-ADP-Ribosylation of PARP1, was also enhanced by 17 β-estradiol under the mechanical load. In conclusion, estrogen application ameliorates the mechanical strain induced cell apoptosis and death in hUSLFs from POP patients. PARP1 might be involved in this protective process, providing novel insights into the mechanical biology of and possible therapies for POP.

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Therapeutic Effects of 17β-Estradiol on Pelvic Organ Prolapse by Inhibiting Mfn2 Expression: An In Vitro Study

Cited by 12 publications

References 37 publications

Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery

Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery

Identification of the genetic basis of sow pelvic organ prolapse

The protective effect of 17 β-estradiol on human uterosacral ligament fibroblasts from postmenopausal women with pelvic organ prolapse

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