Abstract:Intrauterine adhesion (IUA) is characterized by endometrial fibrosis, which ultimately leads to menstrual abnormalities, infertility, and recurrent miscarriages. The Shh/Gli2 pathway plays a critical role in tissue fibrogenesis and regeneration; Gli2 activation induces profibrogenic effects in various tissues, such as the liver and kidney. However, the role of Gli2 in endometrial fibrosis remains unknown. The purpose of this study was to test the hypothesis that activated Gli2 promotes endometrial fibrosis. En… Show more
“…1A ). Because the transcriptional activator GLI2 is elevated in the stroma of IUA tissues 28 , and autophagy dysfunction was evident in the study described above, we further explored the relationship between SHH signaling and autophagy in a human endometrial stromal cell line, T-HESCs. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Numerous studies have demonstrated that the HH pathway induces fibrosis in many organs 7,[21][22][23][24][25][26][27] . We previously found that expression of the HH effector GLI2 was significantly increased in the endometrial stroma of IUA samples and was related to fibrosis severity 28 , indicating aberrant activation of the HH pathway in connection with endometrial fibrosis. However, in vitro results indicated that the HH inhibitor reduced fibrotic protein expression, collagen I, and connective tissue growth factor (CTGF), in human endometrial stromal cells at 48 h (>25%) 28 , while these changes were not fully attributable to the corresponding mRNA expression changes (<25%).…”
Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.
“…1A ). Because the transcriptional activator GLI2 is elevated in the stroma of IUA tissues 28 , and autophagy dysfunction was evident in the study described above, we further explored the relationship between SHH signaling and autophagy in a human endometrial stromal cell line, T-HESCs. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Numerous studies have demonstrated that the HH pathway induces fibrosis in many organs 7,[21][22][23][24][25][26][27] . We previously found that expression of the HH effector GLI2 was significantly increased in the endometrial stroma of IUA samples and was related to fibrosis severity 28 , indicating aberrant activation of the HH pathway in connection with endometrial fibrosis. However, in vitro results indicated that the HH inhibitor reduced fibrotic protein expression, collagen I, and connective tissue growth factor (CTGF), in human endometrial stromal cells at 48 h (>25%) 28 , while these changes were not fully attributable to the corresponding mRNA expression changes (<25%).…”
Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.
Проведение доклинических исследований для оценки безопасности и эффективности лекарственного средства является необходимым условием для его регистрации и внедрения в клиническую практику. Успех данных исследований во многом зависит от выбора животного и способа моделирования определенной патологии. В представленном обзоре методов анализируются данные по моделированию гинекологической патологии на лабораторных животных. В частности, рассмотрены методы воздействия, позволяющие моделировать синдром Ашермана, эндометриоз и хронический эндометрит. Поиск исследований производился в электронной библиотеке PubMed и базe клинических исследований Clinical Trials. В работе приводится характеристика использующихся хирургических вмешательств, физических, химических и инфекционных методов нарушения целостности матки и формирования в органе воспалительного и спаечного процессов. Рассматривается возможность моделирования эндометриоза при помощи стрессового воздействия. Оценена эффективность применения данных стратегий и возможность их дальнейшего использования. Анализ литературы показал, что наиболее оптимальным вариантом для моделирования повреждения матки считается использование крыс-самок в возрасте от 5 до 8 нед. Наиболее воспроизводимым способом имитации патоморфологических механизмов внутриматочной адгезии является повреждение эндометрия 95-процентным этанолом. Наиболее универсальным способом моделирования хронического эндометрита считается подшивание участков эндометрия к париетальной брюшине передней брюшной стенки.
Preclinical studies are performed to assess safety and efficacy of a drug. They are a prerequisite for drug registration and implementation. Success of these studies depends on the choice of the animal and the method of modeling the pathology. This review focuses on modeling gynecological pathologies in preclinical studies. Specifically, the authors addressed experimental impacts for modeling Asherman’s syndrome, endometriosis, and chronic endometritis. The search for literature was conducted in PubMed and Clinical Trials databases. The review describes surgical interventions, physical, chemical, and infectious methods for affecting the uterus integrity and induction of inflammatory and adhesive processes in this organ. A possibility of modeling endometriosis by stress exposures is considered. Effectiveness of these strategies and prospects for their future use were evaluated. According to the analysis of reports the most suitable animal for modeling the uterine damage is 4-8-week-old female rats. The most reproducible way to activate mechanisms of pathomorphological intrauterine adhesion is chemical injury of the endometrium with 95% ethanol. The best approach in modeling chronic endometritis is endometrial and parietal peritoneum stitching.
“…The prevalence of PCOS is 5%-7% among women of childbearing age (19-25 years). Despite being variable in different populations, the main presentations of PCOS include ovulation disorders (oligo or amenorrhea), hyperandrogenism (HA), insulin resistance (IR), and metabolic or psychological disturbances (2,3). To date, the pathogenesis of PCOS has not been well-studied.…”
Recently, a growing body of evidence has suggested that abnormal ovarian angiogenesis, secondary to the imbalance between various angiogenic markers, is involved in the pathogenesis of PCOS, and this has led to the use of various interventions (such as Diane-35) to restore the normal ovarian angiogenesis. Therefore, we conducted the current investigation to determine the role of such markers (endothelial growth factor (VEGF), endostatin (ES), and thrombospondin-1 (TSP-1)) in the pathogenesis of PCOS along with the associated changes in ovarian blood flow in patients with PCOS compared to healthy controls, both before and after a course of oral contraception. A total of 381 patients with PCOS and 98 healthy females of childbearing age were recruited from July 2014 to June 2017 at the Reproductive Center of the Second Affiliated Hospital of Harbin Medical University. The serum levels of VEGF, ES, and TSP-1 were determined by enzyme-linked immunosorbent assay, while ovarian perfusion was measured by the pulsatility index (PI) and resistance index (RI) by using transvaginal color Doppler ultrasound. Repeated analyses were carried out after 3 months of Diane-35 treatment. Post-treatment serum levels of luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio of patients with PCOS decreased significantly (P <0.05). The RI values of most PCOS patients increased after treatment (P<0.05), while PI was significantly increased in all patients (P<0.05). However, variable changes in the serum levels of TSP-1, VEGF, and ES after treatment were observed. Serum VEGF levels showed a negative correlation with serum LH/FSH ratio, T concentration, and ES (P <0.05), while ES levels were negatively correlated with serum T concentrations only (P<0.05). The markers of angiogenesis (VEGF, ES, and TSP-1) were expressed differently among PCOS patients, who also responded differently to the same course of Diane-35 treatment. This field still warrants further investigation to reach a more definitive conclusion.
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