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P K M, C J, T N, F A L, M Harshan H, R S A, S A. Etiology behind canine uterine inertia: Role of uterine expression of MLCK4, MYH2, and PKC genes. Anim Reprod Sci 2023; 256:107298. [PMID: 37499285 DOI: 10.1016/j.anireprosci.2023.107298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023]
Abstract
Dystocia is an obstetrical emergency, and primary uterine inertia (PUI) is the major etiological reason among the more prevalent maternal causes in dogs. The present study involved the relative expression analysis of genes associated with myometrial contraction in medium-sized dog breeds with uterine inertia. Dogs without any progress in the parturition process even after four hours of the onset of labor and the absence of uterine contractions were considered to have complete primary uterine inertia (CPUI, n = 9). Dogs that had expelled at least one fetus and made no further progress in parturition in the absence of active uterine contraction were considered to be experiencing partial primary uterine inertia (PPUI, n = 6). Dogs with the fetal cause of dystocia (FCD), i.e., obstructive dystocia, were taken as the third (n = 7) group. Uterine tissue samples were collected during cesarean section in each group, RNA was isolated, and the relative expression of myometrial ACTA2, ACTG2, MLCK4, MYH2, and PKC genes was analyzed. The MLCK4 gene expression was downregulated in CPUI (P ≤ 0.05) and PPUI (P ≤ 0.01) when compared to FCD. The MYH2 gene expression was downregulated in PPUI in comparison to CPUI (P ≤ 0.01) and FCD (P ≤ 0.05). The PKC gene expression was upregulated in PPUI in comparison to FCD and CPUI (P ≤ 0.05). The downregulation of MLCK4 and MYH2 gene expressions recorded in PPUI indicated the possibility of myometrial defects. The possibility of myometrial defects was also observed in CPUI, but to a lesser degree, suggesting other etiologies.
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Affiliation(s)
- Magnus P K
- Department of Animal Reproduction Gynaecology and Obstetrics, College of Veterinary and Animal Sciences Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India.
| | - Jayakumar C
- Department of Animal Reproduction Gynaecology and Obstetrics, College of Veterinary and Animal Sciences Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India
| | - Naicy T
- Department of Animal Breeding and Genetics, College of Veterinary and Animal Sciences Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India
| | - Lali F A
- Department of Animal Breeding and Genetics, College of Veterinary and Animal Sciences Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India
| | - Hiron M Harshan
- Department of Animal Reproduction Gynaecology and Obstetrics, College of Veterinary and Animal Sciences Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India
| | - Abhilash R S
- Department of Animal Reproduction Gynaecology and Obstetrics, College of Veterinary and Animal Sciences Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India
| | - Ajithkumar S
- University Veterinary Hospital and Teaching Veterinary Clinical Complex, Mannuthy, Kerala Veterinary and Animal Sciences University, Thrissur, Kerala, India
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Abstract
Uterine fibroids (leiomyomas) are present in >75% of women and can cause serious morbidity. They are by far the leading cause of hysterectomy. Fibroids are a complex mixture of cells that include fibroblasts and smooth muscle cells. Rich in extracellular matrix, they typically arise through somatic mutations, most commonly MED12. Their lack of growth inhibition and their ability to have facets of malignancy yet be histologically and biologically benign provide opportunities to explore basic processes. To date, the mechanisms responsible for growth and development of leiomyomas are an enigma. This review provides an overview of current understanding and future directions for clinical and basic research of fibroids.
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Affiliation(s)
- Elizabeth A. Stewart
- 1Division of Reproductive Endocrinology and Infertility, Mayo Clinic, Rochester, Minnesota,2Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota,3Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota,4Department of Surgery, Mayo Clinic, Rochester, Minnesota,5Women’s Health Research Center, Mayo Clinic, Rochester, Minnesota
| | - Romana A. Nowak
- 6Department of Animal Sciences, University of Illinois, Urbana, Illinois,7Institute for Genomic Biology, University of Illinois, Urbana, Illinois
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3
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Physiological and gene expression profiles of leg muscle provide insights into molting-dependent growth of Chinese mitten crab (Eriocheir sinensis). REPRODUCTION AND BREEDING 2021. [DOI: 10.1016/j.repbre.2021.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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4
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Maternal DNA Methylation During Pregnancy: a Review. Reprod Sci 2021; 28:2758-2769. [PMID: 33469876 DOI: 10.1007/s43032-020-00456-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/29/2020] [Indexed: 12/19/2022]
Abstract
Multiple environmental, behavioral, and hereditary factors affect pregnancy. Recent studies suggest that epigenetic modifications, such as DNA methylation (DNAm), affect both maternal and fetal health during the period of gestation. Some of the pregnancy-related risk factors can influence maternal DNAm, thus predisposing both the mother and the neonate to clinical adversities with long-lasting consequences. DNAm alterations in the promoter and enhancer regions modulate gene expression changes which play vital physiological role. In this review, we have discussed the recent advances in our understanding of maternal DNA methylation changes during pregnancy and its associated complications such as gestational diabetes and anemia, adverse pregnancy outcomes like preterm birth, and preeclampsia. We have also highlighted some major gaps and limitations in the area which if addressed might improve our understanding of pregnancy and its associated adverse clinical conditions, ultimately leading to healthy pregnancies and reduction of public health burden.
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Vatner SF, Zhang J, Oydanich M, Berkman T, Naftalovich R, Vatner DE. Healthful aging mediated by inhibition of oxidative stress. Ageing Res Rev 2020; 64:101194. [PMID: 33091597 PMCID: PMC7710569 DOI: 10.1016/j.arr.2020.101194] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/29/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022]
Abstract
The progressive increase in lifespan over the past century carries with it some adversity related to the accompanying burden of debilitating diseases prevalent in the older population. This review focuses on oxidative stress as a major mechanism limiting longevity in general, and healthful aging, in particular. Accordingly, the first goal of this review is to discuss the role of oxidative stress in limiting longevity, and compare healthful aging and its mechanisms in different longevity models. Secondly, we discuss common signaling pathways involved in protection against oxidative stress in aging and in the associated diseases of aging, e.g., neurological, cardiovascular and metabolic diseases, and cancer. Much of the literature has focused on murine models of longevity, which will be discussed first, followed by a comparison with human models of longevity and their relationship to oxidative stress protection. Finally, we discuss the extent to which the different longevity models exhibit the healthful aging features through physiological protective mechanisms related to exercise tolerance and increased β-adrenergic signaling and also protection against diabetes and other metabolic diseases, obesity, cancer, neurological diseases, aging-induced cardiomyopathy, cardiac stress and osteoporosis.
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Affiliation(s)
- Stephen F Vatner
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey, USA.
| | - Jie Zhang
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey, USA
| | - Marko Oydanich
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey, USA
| | - Tolga Berkman
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey, USA
| | - Rotem Naftalovich
- Department of Anesthesiology, New Jersey Medical School, Newark, New Jersey, USA
| | - Dorothy E Vatner
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey, USA.
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6
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Akbas M, Koyuncu FM. The Utility of Myometrial and Cervical Ultrasound Shear Wave Elastography in the Diagnosis of Ectopic Pregnancy. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:2215-2221. [PMID: 32507698 DOI: 10.1016/j.ultrasmedbio.2020.04.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 06/11/2023]
Abstract
We aimed to assess the potential utility of myometrial and cervical elasticity measurement in the diagnosis of ectopic pregnancy (EP), which could facilitate the diagnosis process. Myometrial and cervical elasticity values were measured in women with EP, women with early intrauterine pregnancy (IP) and non-pregnant women. Transabdominal point shear wave elastography (pSWE) was used for elasticity measurements. A reliability study was performed in 20 patients of the non-pregnant group. Cervical pSWE showed poor reliability and high measurement failure rate; thus, we excluded cervical elasticity assessment from the study. In this study, 32 women with EP, 28 women with early IP and 38 non-pregnant women were enrolled for myometrial elasticity assessment by pSWE. Myometrial elasticity values were statistically significantly lower in EP (8.31 kPa [5.1-27]) and early IP (8.83 kPa [4.5-46.2]) groups than in non-pregnant women (14.85 kPa [5.1-28]) (p = 0.003). However, myometrial pSWE results were not significantly different between EP and early IP groups. In light of this data, quantitative assessment of the uterus elasticity using pSWE does not seem to be an adequate diagnostic method for EP.
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Affiliation(s)
- Murat Akbas
- Manisa Celal Bayar University, Department of Obstetrics and Gynecology, Perinatology Division, Manisa, Turkey.
| | - Faik Mumtaz Koyuncu
- Manisa Celal Bayar University, Department of Obstetrics and Gynecology, Perinatology Division, Manisa, Turkey
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7
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Zaobidna E, Kiezun M, Dobrzyn K, Szeszko K, Rytelewska E, Kisielewska K, Gudelska M, Bors K, Kopij G, Szymanska K, Kaminska B, Kaminski T, Smolinska N. The influence of orexin B on the transcriptome profile of porcine myometrial explants during early implantation. Theriogenology 2020; 156:205-213. [PMID: 32755720 DOI: 10.1016/j.theriogenology.2020.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 01/04/2023]
Abstract
This study aimed to determine the effect of orexin B (OXB) on the global expression pattern and the relationships among differentially expressed genes (DE-genes) in the transcriptome of myometrial explants during the early implantation period in the pig (day 15 of pregnancy). The changes in the transcriptome profile of the porcine myometrium were investigated using the Porcine (V2) Two-colour Gene Expression Microarray, 4 × 44. An analysis of the data from the microarray experiment revealed that 1540 DE-genes were affected by OXB, of which 1135 exhibited fold changes (FC) greater than 1.2 (P < 0.05). Among these, 576 genes were up-regulated and 559 genes were down-regulated. Among the affected biological processes in the myometrial tissue, 76 were enhanced and 31 were suppressed. Furthermore, the differential expression of nine genes, related to the regulation of reproductive functions and metabolic homeostasis, was confirmed by quantitative RT-PCR. A functional analysis of the relationships between DE-genes indicated that OXB interacts with the genes involved in the processes such as the inflammatory response, the response to interleukin-6, cytokine receptor activity, the regulation of cell activation, growth factor receptor binding, lipid modification and the steroid metabolic process. An analysis of DE-genes and their functional relationships suggests that OXB could be involved in the mechanisms such as the regulation of cell proliferation and development, inhibition of contractility, regulation of programmed cell death, and the development of blood vessels, all of which facilitate implantation.
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Affiliation(s)
- Ewa Zaobidna
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Kamil Dobrzyn
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Karol Szeszko
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Katarzyna Kisielewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Marlena Gudelska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Kinga Bors
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Grzegorz Kopij
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Karolina Szymanska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Barbara Kaminska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn-Kortowo, Poland.
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Milesi MM, Durando M, Lorenz V, Gastiazoro MP, Varayoud J. Postnatal exposure to endosulfan affects uterine development and fertility. Mol Cell Endocrinol 2020; 511:110855. [PMID: 32437785 DOI: 10.1016/j.mce.2020.110855] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 03/30/2020] [Accepted: 04/29/2020] [Indexed: 12/16/2022]
Abstract
Endosulfan is an organochlorine pesticide (OCP) used in large-scale agriculture for controlling a variety of insects and mites that attack food and non-food crops. Although endosulfan has been listed in the Stockholm Convention as a persistent organic pollutant to be worldwide banned, it is still in use in some countries. Like other OCPs, endosulfan is bioaccumulative, toxic and persistent in the environment. Human unintentional exposure may occur through air inhalation, dietary, skin contact, as well as, via transplacental route and breast feeding. Due to its lipophilic nature, endosulfan is rapidly absorbed into the gastrointestinal tract and bioaccumulates in the fatty tissues. Similar to other OCPs, endosulfan has been classified as an endocrine disrupting chemical (EDC). Endocrine action of endosulfan on development and reproductive function of males has been extensively discussed; however, endosulfan effects on the female reproductive tract have received less attention. This review provides an overview of: i) the fate and levels of endosulfan in the environment and human population, ii) the potential estrogenic properties of endosulfan in vitro and in vivo, iii) its effects on uterine development, and iv) the long-term effects on female fertility and uterine functional differentiation during early gestation.
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Affiliation(s)
- M M Milesi
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Casilla de Correo 242, 3000, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina.
| | - M Durando
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Casilla de Correo 242, 3000, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
| | - V Lorenz
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Casilla de Correo 242, 3000, Santa Fe, Argentina
| | - M P Gastiazoro
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Casilla de Correo 242, 3000, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
| | - J Varayoud
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Casilla de Correo 242, 3000, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
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9
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Wu SP, Anderson ML, Wang T, Zhou L, Emery OM, Li X, DeMayo FJ. Dynamic transcriptome, accessible genome, and PGR cistrome profiles in the human myometrium. FASEB J 2019; 34:2252-2268. [PMID: 31908010 DOI: 10.1096/fj.201902654r] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/20/2019] [Accepted: 11/23/2019] [Indexed: 02/04/2023]
Abstract
The myometrium undergoes structural and functional remodeling during pregnancy. We hypothesize that myometrial genomic elements alter correspondingly in preparation for parturition. Human myometrial tissues from nonpregnant (NP) and term pregnant (TP) human subjects were examined by RNAseq, ATACseq, and PGR ChIPseq assays to profile transcriptome, assessible genome, and PGR occupancy. NP and TP specimens exhibit 2890 differentially expressed genes, reflecting an increase of metabolic, inflammatory, and PDGF signaling, among others, in adaptation to pregnancy. At the epigenome level, patterns of accessible genome change between NP and TP myometrium, leading to the altered enrichment of binding motifs for hormone and muscle regulators such as the progesterone receptor (PGR), Krüppel-like factors, and MEF2A transcription factors. PGR genome occupancy exhibits a significant difference between the two stages of the myometrium, concomitant with distinct transcriptomic profiles including genes such as ENO1, LHDA, and PLCL1 in the glycolytic and calcium signaling pathways. Over-representation of SRF, MYOD, and STAT binding motifs in PGR occupying sites further suggests interactions between PGR and major muscle regulators for myometrial gene expression. In conclusion, changes in accessible genome and PGR occupancy are part of the myometrial remodeling process and may serve as mechanisms to formulate the state-specific transcriptome profiles.
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Affiliation(s)
- San-Pin Wu
- Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC
| | - Matthew L Anderson
- Department of Obstetrics & Gynecology, University of South Florida Morsani College of Medicine and Moffitt Cancer Center, Tampa, FL
| | - Tianyuan Wang
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC
| | - Lecong Zhou
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC
| | - Olivia M Emery
- Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC
| | - Xilong Li
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Francesco J DeMayo
- Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC
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Kranz TM, Lent KL, Miller KE, Chao MV, Brenowitz EA. Rapamycin blocks the neuroprotective effects of sex steroids in the adult birdsong system. Dev Neurobiol 2019; 79:794-804. [PMID: 31509642 DOI: 10.1002/dneu.22719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/23/2019] [Accepted: 09/05/2019] [Indexed: 11/06/2022]
Abstract
In adult songbirds, the telencephalic song nucleus HVC and its efferent target RA undergo pronounced seasonal changes in morphology. In breeding birds, there are increases in HVC volume and total neuron number, and RA neuronal soma area compared to nonbreeding birds. At the end of breeding, HVC neurons die through caspase-dependent apoptosis and thus, RA neuron size decreases. Changes in HVC and RA are driven by seasonal changes in circulating testosterone (T) levels. Infusing T, or its metabolites 5α-dihydrotestosterone (DHT) and 17 β-estradiol (E2), intracerebrally into HVC (but not RA) protects HVC neurons from death, and RA neuron size, in nonbreeding birds. The phosphoinositide 3-kinase (PI3K)-Akt (a serine/threonine kinase)-mechanistic target of rapamycin (mTOR) signaling pathway is a point of convergence for neuroprotective effects of sex steroids and other trophic factors. We asked if mTOR activation is necessary for the protective effect of hormones in HVC and RA of adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii). We transferred sparrows from breeding to nonbreeding hormonal and photoperiod conditions to induce regression of HVC neurons by cell death and decrease of RA neuron size. We infused either DHT + E2, DHT + E2 plus the mTOR inhibitor rapamycin, or vehicle alone in HVC. Infusion of DHT + E2 protected both HVC and RA neurons. Coinfusion of rapamycin with DHT + E2, however, blocked the protective effect of hormones on HVC volume and neuron number, and RA neuron size. These results suggest that activation of mTOR is an essential downstream step in the neuroprotective cascade initiated by sex steroid hormones in the forebrain.
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Affiliation(s)
- Thorsten M Kranz
- Department of Psychiatry, Skirball Institute of Biomolecular Medicine, Langone Medical Center, New York University, New York, New York
| | - Karin L Lent
- Departments of Psychology and Biology, Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington
| | - Kimberly E Miller
- Departments of Psychology and Biology, Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington
| | - Moses V Chao
- Department of Psychiatry, Skirball Institute of Biomolecular Medicine, Langone Medical Center, New York University, New York, New York
| | - Eliot A Brenowitz
- Departments of Psychology and Biology, Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington
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11
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Bhatti M, Dinn S, Miskiewicz EI, MacPhee DJ. Expression of heat shock factor 1, heat shock protein 90 and associated signaling proteins in pregnant rat myometrium: Implications for myometrial proliferation. Reprod Biol 2019; 19:374-385. [PMID: 31522994 DOI: 10.1016/j.repbio.2019.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 09/03/2019] [Accepted: 09/05/2019] [Indexed: 01/07/2023]
Abstract
During pregnancy and labour the myometrium undergoes structural and physiological adaptations as part of a program of development. Heat shock factor 1 (HSF1) is a master regulator of both stress and developmental processes. A noted HSF1-induced gene is the 90 kDa heat shock protein (HSP90), which acts as a chaperone and regulator of cellular processes. Immunoblot analysis demonstrated HSF1 expression levels in pregnant rat myometrium on gestational day (d) 6 were maintained at a significantly higher level compared with d12 to post-partum (PP) time points (P < 0.05), while expression on d12 was significantly higher compared to d15 and d19. The transcriptionally active form pSer230-HSF1 was detected at a significantly greater level at d6 compared with d21 and d23 time points and also at d12 compared with d21, d22 and 23 (labour). Similarly, phosphorylated (P)-HSP90AA1 protein detection was significantly greater on d6 compared to d19 to d23 time points and on d12 compared with d15 to PP time points. In contrast, P-HSP90AB1 showed significantly greater detection levels on d12 compared with d15 while levels on d22 were significantly higher compared to d15, d17 and d19. Immunofluorescence analysis demonstrated that total HSF1 and HSP90 were localized mainly in the cytoplasm of myometrial cells with some detection of HSF1 in nuclei. This work advances our scientific knowledge of the myometrium during pregnancy and the expression profiles of HSF1 and HSP90 within the proliferative phase of myometrial programming suggests a role for them in this period of hyperplasia and myometrial adaptation.
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Affiliation(s)
- Masooma Bhatti
- Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada; One Reproductive Health Research Group, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada
| | - Sarah Dinn
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada
| | - Ewa I Miskiewicz
- Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada; One Reproductive Health Research Group, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada
| | - Daniel J MacPhee
- Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada; One Reproductive Health Research Group, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
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12
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Alarcón R, Varayoud J, Luque EH, Milesi MM. Effect of neonatal exposure to endosulfan on myometrial adaptation during early pregnancy and labor in rats. Mol Cell Endocrinol 2019; 491:110435. [PMID: 31029737 DOI: 10.1016/j.mce.2019.04.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/13/2019] [Accepted: 04/22/2019] [Indexed: 12/28/2022]
Abstract
Proper myometrial adaptation during gestation is crucial for embryo implantation, pregnancy maintenance and parturition. Previously, we reported that neonatal exposure to endosulfan alters uterine development and induces implantation failures. The present work investigates the effects of endosulfan exposure on myometrial differentiation at the pre-implantation period, and myometrial activation during labor. Newborn female rats were s.c. injected with corn oil (vehicle) or 600 μg/kg/day of endosulfan (Endo600) on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate: i) the myometrial differentiation on gestational day 5 (GD5, pre-implantation period), by assessment myometrial histomorphology, smooth muscle cells (SMCs) proliferation, and expression of proteins involved in myometrial adaptation for embryo implantation (steroid receptors, Wnt7a and Hoxa10); ii) the timing of parturition and myometrial activation during labor by determining the uterine expression of contraction-associated genes (oxytocin receptor, OTXR; prostaglandin F2α receptor, PTGFR and connexin-43, Cx-43). Endosulfan decreased the thickness of both myometrial layers, with a concomitant decrease in the collagen remodeling. Blood vessels relative area in the interstitial connective tissue between muscle layers was also decreased. Endo600 group showed lower myometrial proliferation in association with a downregulation of Wnt7a and Hoxa10. Although in all females labor occurred on GD23, the exposure to endosulfan altered the timing of parturition, by inducing advancement in the initiation of labor. This alteration was associated with an increased uterine expression of OTXR, PTGFR and Cx-43. In conclusion, neonatal exposure to endosulfan produced long-term effects affecting myometrial adaptation during early pregnancy and labor. These alterations could be associated with the aberrant effects of endosulfan on the implantation process and the timing of parturition.
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Affiliation(s)
- Ramiro Alarcón
- Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Jorgelina Varayoud
- Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Enrique H Luque
- Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - María M Milesi
- Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
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13
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Trichostatin A inhibits uterine histomorphology alterations induced by cigarette smoke exposure in mice. Life Sci 2019; 228:112-120. [DOI: 10.1016/j.lfs.2019.04.069] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/28/2019] [Accepted: 04/30/2019] [Indexed: 01/07/2023]
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14
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Progesterone Via its Type-A Receptor Promotes Myometrial Gap Junction Coupling. Sci Rep 2017; 7:13357. [PMID: 29042599 PMCID: PMC5645358 DOI: 10.1038/s41598-017-13488-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 09/20/2017] [Indexed: 12/17/2022] Open
Abstract
Effective labour contractions require synchronization of myometrial cells through gap junctions (GJs). Clasically, progesterone (P4) is known to inhibit the expression of connexin-43 (Cx43, major component of GJs) and GJ formation in myometrium. Our current study is based on a striking observation that challenges this dogma. We observed conspicuous differences in the intracellular localization of Cx43 protein in PRA versus PRB expressing myocytes. Thus in P4 stimulated PRA cells Cx43 protein forms GJs, whereas in PRB cells the forward trafficking of Cx43 and GJ formation is inhibited even when Cx43 is overexpressed. We found that P4, via PRA/B, differentially regulates Cx43 translation to generate a Cx43-20 K isoform, which facilitates the transport of full length Cx43 to plasma membrane. The P4 mediated regulation of Cx43 trafficking and GJ formation occurs via non-genomic pathway and involves the regulation of mTOR signaling since inhibition of this pathway restored the Cx43 trafficking defect in PRB cells. We propose that PRA is a master regulator of Cx43 expression, GJ formation and myocyte connectivity/synchronization for labour.
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15
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Berkane N, Liere P, Oudinet JP, Hertig A, Lefèvre G, Pluchino N, Schumacher M, Chabbert-Buffet N. From Pregnancy to Preeclampsia: A Key Role for Estrogens. Endocr Rev 2017; 38:123-144. [PMID: 28323944 DOI: 10.1210/er.2016-1065] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 02/28/2017] [Indexed: 02/08/2023]
Abstract
Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.
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Affiliation(s)
- Nadia Berkane
- Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Genève, Switzerland.,U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Philippe Liere
- U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Jean-Paul Oudinet
- U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Alexandre Hertig
- Department of Nephrology, Tenon Hospital, APHP, 75020 Paris, France.,University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Unité Mixte de Recherche Scientifique 1155, F-75020 Paris, France
| | - Guillaume Lefèvre
- University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Department of Biochemistry and Hormonology, Tenon Hospital, APHP, F-75020 Paris, France
| | - Nicola Pluchino
- Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Genève, Switzerland
| | | | - Nathalie Chabbert-Buffet
- University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Department of Obstetrics, Gynecology and Reproductive Medicine, Tenon Hospital, APHP, F-75020 Paris, France.,INSERM, UMR-S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France
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16
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Yen CF, Huang SJ, Lee CL, Wang HS, Liao SK. Molecular Characteristics of the Endometrium in Uterine Adenomyosis and Its Biochemical Microenvironment. Reprod Sci 2017; 24:1346-1361. [PMID: 28183227 DOI: 10.1177/1933719117691141] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Adenomyosis, which manifests with focally or diffusely scattered endometrial tissue within the uterine myometrium, is an endometriosis-like disease with controversial pathogenesis and compromised reproductive outcomes. This review, including the in vitro and in vivo studies performed on human or mouse models, is aimed to summarize the specific molecular characteristics of endometrium in the biochemical microenvironments of uterine adenomyosis. Many studies attributed the endometrium as the main cause of pathogenesis, with evidence of differential genetic expression and/or epigenetic modulation as well as estrogen-induced epithelial-mesenchymal transition. However, some studies indicated that the myometrium could play a role in the development of disease, based on findings of smooth muscle metaplasia and/or fibroblast-to-myofibroblast transdifferentiation by the influence of local biochemical factors. To date, it remains unclear whether adenomyosis is a genetically determined or a microenvironmentally induced disorder or whether the dysregulation of local factors may elicit the alteration of genetic expression in the endometrium. Similarly, it is uncertain whether the endometrial characteristics would remain consistent or could change along with a woman's reproductive life. Further longitudinal studies of the epigenetic controls or system biology are needed to elucidate the pathogenesis. Discovery of effective conservative treatments to improve the reproductive outcomes of patients with adenomyosis is still warranted.
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Affiliation(s)
- Chih-Feng Yen
- 1 Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan.,2 Department of Obstetrics and Gynecology, Chang Gung University College of Medicine, Kwei-Shan, Tao-Yuan, Taiwan.,3 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
| | - S Joseph Huang
- 4 Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.,5 Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chyi-Long Lee
- 2 Department of Obstetrics and Gynecology, Chang Gung University College of Medicine, Kwei-Shan, Tao-Yuan, Taiwan.,6 Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Hsin-Shih Wang
- 1 Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan.,2 Department of Obstetrics and Gynecology, Chang Gung University College of Medicine, Kwei-Shan, Tao-Yuan, Taiwan.,3 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
| | - Shuen-Kuei Liao
- 2 Department of Obstetrics and Gynecology, Chang Gung University College of Medicine, Kwei-Shan, Tao-Yuan, Taiwan.,7 The PhD Program of Cancer Biology and Drug Discovery, Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan
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17
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The Potential Functions of Small Heat Shock Proteins in the Uterine Musculature during Pregnancy. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2017; 222:95-116. [PMID: 28389752 DOI: 10.1007/978-3-319-51409-3_5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The small heat shock protein B (HSPB) family is comprised of eleven members with many being induced by physiological stressors. In addition to being molecular chaperones, it is clear these proteins also play important roles in cell death regulation, cytoskeletal rearrangements, and immune system activation. These processes are important for the uterine smooth muscle or myometrium during pregnancy as it changes from a quiescent tissue, during the majority of pregnancy, to a powerful and contractile tissue at labor. The initiation and progression of labor within the myometrium also appears to require an inflammatory response as it is infiltrated by immune cells and it produces pro-inflammatory mediators. This chapter summarizes current knowledge on the expression of HSPB family members in the myometrium during pregnancy and speculates on the possible roles of these proteins during myometrial programming and transformation of the myometrium into a possible immune regulatory tissue.
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18
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Park J, Shin H, Song H, Lim HJ. Autophagic regulation in steroid hormone-responsive systems. Steroids 2016; 115:177-181. [PMID: 27643453 DOI: 10.1016/j.steroids.2016.09.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 08/23/2016] [Accepted: 09/14/2016] [Indexed: 01/10/2023]
Abstract
Two female sex steroid hormones, estrogen and progesterone, are crucial regulators of many physiological functions of reproductive organs. These two hormones are versatile factors linking growth, differentiation, metabolism, and death of cells in the uterus. In recent years, it has become evident that autophagy is involved in the effects of estrogen and progesterone on various cellular events in reproductive organs. Autophagy is the self-eating catabolic process which is linked to cell survival and death in many contexts. In this review, we focus on the new findings concerning the regulation of autophagic response by sex steroid hormones in responsive target organs. We also attempt to further expand our insight into intracellular signaling mediators governing this regulation.
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Affiliation(s)
- Jaekyoung Park
- Department of Biomedical Science & Technology, Konkuk University, Seoul, Republic of Korea
| | - Hyejin Shin
- Department of Biomedical Science & Technology, Konkuk University, Seoul, Republic of Korea
| | - Haengseok Song
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea.
| | - Hyunjung J Lim
- Department of Biomedical Science & Technology, Konkuk University, Seoul, Republic of Korea; Department of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea.
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19
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Zhou C, Zhang T, Liu F, Zhou J, Ni X, Huo R, Shi Z. The differential expression of mRNAs and long noncoding RNAs between ectopic and eutopic endometria provides new insights into adenomyosis. MOLECULAR BIOSYSTEMS 2016; 12:362-70. [PMID: 26662114 DOI: 10.1039/c5mb00733j] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Adenomyosis, defined as ectopic endometrial tissue within the myometrium, can often be misdiagnosed as multiple uterine leiomyomata or endometrial thickening. We therefore performed a combined mRNA and long noncoding (lnc)RNA microarray and bioinformatic analysis of eutopic and ectopic endometria in women with adenomyosis to better understand its pathogenesis and help in the development of a semi-invasive diagnostic test. A total of 586 mRNAs were increased and 305 mRNAs decreased in the ectopic endometrium of adenomyosis compared with the eutopic endometrium, while 388 lncRNA transcripts were up-regulated and 188 down-regulated in ectopic compared with paired eutopic endometrial tissue. Bioinformatic analysis suggested a series of metabolic and molecular abnormalities in adenomyosis, which have many similarities with endometriosis. Furthermore, our study constitutes the first known report of lncRNA expression patterns in human adenomyosis ectopic and eutopic endometrial tissue.
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Affiliation(s)
- Cheng Zhou
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
| | - Ting Zhang
- Wuxi Maternity and Child Health Hospital, Wuxi city, China
| | - Fei Liu
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
| | - Ji Zhou
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
| | - Xiaobei Ni
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
| | - Ran Huo
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
| | - Zhonghua Shi
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China. and State Key Laboratory of Reproductive Medicine, Nanjing Maternity and Child Health Hospital, Nanjing Medical University, Nanjing, China
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20
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Kim YJ, Tamadon A, Park HT, Kim H, Ku SY. The role of sex steroid hormones in the pathophysiology and treatment of sarcopenia. Osteoporos Sarcopenia 2016; 2:140-155. [PMID: 30775480 PMCID: PMC6372754 DOI: 10.1016/j.afos.2016.06.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/09/2016] [Accepted: 06/17/2016] [Indexed: 12/18/2022] Open
Abstract
Sex steroids influence the maintenance and growth of muscles. Decline in androgens, estrogens and progesterone by aging leads to the loss of muscular function and mass, sarcopenia. These steroid hormones can interact with different signaling pathways through their receptors. To date, sex steroid hormone receptors and their exact roles are not completely defined in skeletal and smooth muscles. Although numerous studies focused on the effects of sex steroid hormones on different types of cells, still many unexplained molecular mechanisms in both skeletal and smooth muscle cells remain to be investigated. In this paper, many different molecular mechanisms that are activated or inhibited by sex steroids and those that influence the growth, proliferation, and differentiation of skeletal and smooth muscle cells are reviewed. Also, the similarities of cellular and molecular pathways of androgens, estrogens and progesterone in both skeletal and smooth muscle cells are highlighted. The reviewed signaling pathways and participating molecules can be targeted in the future development of novel therapeutics.
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Affiliation(s)
- Yong Jin Kim
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, South Korea
| | - Amin Tamadon
- Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Hyun Tae Park
- Department of Obstetrics and Gynecology, Korea University Anam Hospital, Korea University College of Medicine, South Korea
| | - Hoon Kim
- Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Seung-Yup Ku
- Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, South Korea
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21
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Sotiriadis G, Dodagatta-Marri E, Kouser L, Alhamlan FS, Kishore U, Karteris E. Surfactant Proteins SP-A and SP-D Modulate Uterine Contractile Events in ULTR Myometrial Cell Line. PLoS One 2015; 10:e0143379. [PMID: 26641881 PMCID: PMC4671565 DOI: 10.1371/journal.pone.0143379] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 11/04/2015] [Indexed: 01/27/2023] Open
Abstract
Pulmonary surfactant proteins SP-A and SP-D are pattern recognition innate immune molecules. However, there is extrapulmonary existence, especially in the amniotic fluid and at the feto-maternal interface. There is sufficient evidence to suggest that SP-A and SP-D are involved in the initiation of labour. This is of great importance given that preterm birth is associated with increased mortality and morbidity. In this study, we investigated the effects of recombinant forms of SP-A and SP-D (rhSP-A and rhSP-D, the comprising of trimeric lectin domain) on contractile events in vitro, using a human myometrial cell line (ULTR) as an experimental model. Treatment with rhSP-A or rhSP-D increased the cell velocity, distance travelled and displacement by ULTR cells. rhSP-A and rhSP-D also affected the contractile response of ULTRs when grown on collagen matrices showing reduced surface area. We investigated this effect further by measuring contractility-associated protein (CAP) genes. Treatment with rhSP-A and rhSP-D induced expression of oxytocin receptor (OXTR) and connexin 43 (CX43). In addition, rhSP-A and rhSP-D were able to induce secretion of GROα and IL-8. rhSP-D also induced the expression of IL-6 and IL-6 Ra. We provide evidence that SP-A and SP-D play a key role in modulating events prior to labour by reconditioning the human myometrium and in inducing CAP genes and pro-inflammatory cytokines thus shifting the uterus from a quiescent state to a contractile one.
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Affiliation(s)
- Georgios Sotiriadis
- Centre for Infection, Immunity and Disease Mechanisms, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Eswari Dodagatta-Marri
- Centre for Infection, Immunity and Disease Mechanisms, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Lubna Kouser
- Centre for Infection, Immunity and Disease Mechanisms, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Fatimah S. Alhamlan
- Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Uday Kishore
- Centre for Infection, Immunity and Disease Mechanisms, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Emmanouil Karteris
- Centre for Infection, Immunity and Disease Mechanisms, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
- Institute of Environment, Heath and Societies, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
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22
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Bloise E, Ortiga-Carvalho TM, Reis FM, Lye SJ, Gibb W, Matthews SG. ATP-binding cassette transporters in reproduction: a new frontier. Hum Reprod Update 2015; 22:164-81. [PMID: 26545808 DOI: 10.1093/humupd/dmv049] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 10/19/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The transmembrane ATP-binding cassette (ABC) transporters actively efflux an array of clinically relevant compounds across biological barriers, and modulate biodistribution of many physiological and pharmacological factors. To date, over 48 ABC transporters have been identified and shown to be directly and indirectly involved in peri-implantation events and fetal/placental development. They efflux cholesterol, steroid hormones, vitamins, cytokines, chemokines, prostaglandins, diverse xenobiotics and environmental toxins, playing a critical role in regulating drug disposition, immunological responses and lipid trafficking, as well as preventing fetal accumulation of drugs and environmental toxins. METHODS This review examines ABC transporters as important mediators of placental barrier functions and key reproductive processes. Expression, localization and function of all identified ABC transporters were systematically reviewed using PubMed and Google Scholar websites to identify relevant studies examining ABC transporters in reproductive tissues in physiological and pathophysiological states. Only reports written in English were incorporated with no restriction on year of publication. While a major focus has been placed on the human, extensive evidence from animal studies is utilized to describe current understanding of the regulation and function of ABC transporters relevant to human reproduction. RESULTS ABC transporters are modulators of steroidogenesis, fertilization, implantation, nutrient transport and immunological responses, and function as 'gatekeepers' at various barrier sites (i.e. blood-testes barrier and placenta) against potentially harmful xenobiotic factors, including drugs and environmental toxins. These roles appear to be species dependent and change as a function of gestation and development. The best-described ABC transporters in reproductive tissues (primarily in the placenta) are the multidrug transporters p-glycoprotein and breast cancer-related protein, the multidrug resistance proteins 1 through 5 and the cholesterol transporters ABCA1 and ABCG1. CONCLUSIONS The ABC transporters have various roles across multiple reproductive tissues. Knowledge of efflux direction, tissue distribution, substrate specificity and regulation of the ABC transporters in the placenta and other reproductive tissues is rapidly expanding. This will allow better understanding of the disposition of specific substrates within reproductive tissues, and facilitate development of novel treatments for reproductive disorders as well as improved approaches to protecting the developing fetus.
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Affiliation(s)
- E Bloise
- Laboratory of Translational Endocrinology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - T M Ortiga-Carvalho
- Laboratory of Translational Endocrinology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - F M Reis
- Division of Human Reproduction, Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - S J Lye
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 Department Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - W Gibb
- Department of Obstetrics & Gynecology, University of Ottawa, Ottawa, ON, Canada Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - S G Matthews
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 Department Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
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23
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Carrarelli P, Yen CF, Arcuri F, Funghi L, Tosti C, Wang TH, Huang JS, Petraglia F. Myostatin, follistatin and activin type II receptors are highly expressed in adenomyosis. Fertil Steril 2015; 104:744-52.e1. [DOI: 10.1016/j.fertnstert.2015.05.032] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/13/2015] [Accepted: 05/24/2015] [Indexed: 10/23/2022]
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24
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Marsh NM, Wareham A, White BG, Miskiewicz EI, Landry J, MacPhee DJ. HSPB8 and the Cochaperone BAG3 Are Highly Expressed During the Synthetic Phase of Rat Myometrium Programming During Pregnancy. Biol Reprod 2015; 92:131. [PMID: 25904010 DOI: 10.1095/biolreprod.114.125401] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 04/09/2015] [Indexed: 12/17/2022] Open
Abstract
The small heat shock protein (HSP) B family of proteins are a group of molecular chaperones that enable tissues to adapt to changes in their local environments during differentiation, stress, or disease conditions. The objective of this research was to characterize the expression of HSPB8 and its cochaperone Bcl2-associated athanogene 3 (BAG3) in nonpregnant (NP) and pregnant rat myometrium during myometrial programming. Rat myometrium was collected from NP and pregnant rats as well as 1 day postpartum (PP) and samples prepared for immunoblot and immunofluorescence analysis. Immunoblot analysis determined that HSPB8 protein expression was significantly elevated at Day (D) 15, D17, and D19 compared to expression at NP and D6, while BAG3 expression was significantly elevated at D15 compared to NP, and D17 compared to NP, D6, D23, and PP time points (P < 0.05). In situ, HSPB8 and BAG3 were predominantly localized to myometrial cells throughout pregnancy, with intense cytoplasmic HSPB8 and BAG3 detection on D15 and D17 in both longitudinal and circular muscle layers. Immunoblot analysis of HSPB8 and BAG3 protein expression in myometrium from unilateral pregnancies also revealed that expression of both proteins was significantly increased at D15 in gravid compared to nongravid horns. Thus, HSPB8 and BAG3 are highly expressed during the synthetic phase of myometrial differentiation marked by initiation of uterine distension and myometrial hypertrophy. HSPB8 and BAG3 could be regulators of the protein quality control required for this process.
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Affiliation(s)
- Noelle M Marsh
- Division of Biomedical Sciences, Health Sciences Centre, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Angela Wareham
- Division of Biomedical Sciences, Health Sciences Centre, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Bryan G White
- Okanagan College-Salmon Arm Campus, Salmon Arm, British Columbia, Canada
| | - Ewa I Miskiewicz
- Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Jacques Landry
- Centre de Recherche en Cancerologie de l'Universite Laval, L'Hotel-Dieu de Quebec, Quebec, Quebec, Canada
| | - Daniel J MacPhee
- One Reproductive Health Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Agrawal V, Jaiswal MK, Mallers T, Katara GK, Gilman-Sachs A, Beaman KD, Hirsch E. Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor. Sci Rep 2015; 5:9410. [PMID: 25797357 PMCID: PMC4369745 DOI: 10.1038/srep09410] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 03/02/2015] [Indexed: 12/28/2022] Open
Abstract
Cellular organelles and proteins are degraded and recycled through autophagy, a process during which vesicles known as autophagosomes fuse with lysosomes. Altered autophagy occurs in various diseases, but its role in preterm labor (PTL) is unknown. We investigated the role of autophagic flux in two mouse models of PTL compared to controls: 1) inflammation-induced PTL (IPTL), induced by toll-like receptor agonists; and 2) non-inflammation (hormonally)-induced PTL (NIPTL). We demonstrate that the autophagy related genes Atg4c and Atg7 (involved in the lipidation of microtubule-associated protein 1 light chain 3 (LC3) B-I to the autophagosome-associated form, LC3B-II) decrease significantly in uterus and placenta during IPTL but not NIPTL. Autophagic flux is altered in IPTL, as shown by the accumulation of LC3B paralogues and diminishment of lysosome associated membrane protein (LAMP)-1, LAMP-2 and the a2 isoform of V-ATPase (a2V, an enzyme involved in lysosome acidification). These alterations in autophagy are associated with increased activation of NF-κB and proinflammatory cytokines/chemokines in both uterus and placenta. Similar changes are seen in macrophages exposed to TLR ligands and are enhanced with blockade of a2V. These novel findings represent the first evidence of an association between altered autophagic flux and hyper-inflammation and labor in IPTL.
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Affiliation(s)
- Varkha Agrawal
- Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL
| | - Mukesh K. Jaiswal
- Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Timothy Mallers
- Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Gajendra K. Katara
- Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Alice Gilman-Sachs
- Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Kenneth D. Beaman
- Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Emmet Hirsch
- Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL
- Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL
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Sohrabji F. Estrogen-IGF-1 interactions in neuroprotection: ischemic stroke as a case study. Front Neuroendocrinol 2015; 36:1-14. [PMID: 24882635 PMCID: PMC4247812 DOI: 10.1016/j.yfrne.2014.05.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 05/15/2014] [Accepted: 05/16/2014] [Indexed: 12/25/2022]
Abstract
The steroid hormone 17b-estradiol and the peptide hormone insulin-like growth factor (IGF)-1 independently exert neuroprotective actions in neurologic diseases such as stroke. Only a few studies have directly addressed the interaction between the two hormone systems, however, there is a large literature that indicates potentially greater interactions between the 17b-estradiol and IGF-1 systems. The present review focuses on key issues related to this interaction including IGF-1 and sex differences and common activation of second messenger systems. Using ischemic stroke as a case study, this review also focuses on independent and cooperative actions of estrogen and IGF-1 on neuroprotection, blood brain barrier integrity, angiogenesis, inflammation and post-stroke epilepsy. Finally, the review also focuses on the astrocyte, a key mediator of post stroke repair, as a local source of 17b-estradiol and IGF-1. This review thus highlights areas where significant new research is needed to clarify the interactions between these two neuroprotectants.
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Affiliation(s)
- Farida Sohrabji
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, TAMHSC College of Medicine, Bryan, TX 77807, United States.
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27
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Gong JS, Kim GJ. The role of autophagy in the placenta as a regulator of cell death. Clin Exp Reprod Med 2014; 41:97-107. [PMID: 25309853 PMCID: PMC4192457 DOI: 10.5653/cerm.2014.41.3.97] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 05/28/2014] [Accepted: 08/04/2014] [Indexed: 12/24/2022] Open
Abstract
The placenta is a temporary fetomaternal organ capable of supporting fetal growth and development during pregnancy. In particular, abnormal development and dysfunction of the placenta due to cha nges in the proliferation, differentiation, cell death, and invasion of trophoblasts induce several gynecological diseases as well as abnormal fetal development. Autophagy is a catalytic process that maintains cellular structures by recycling building blocks derived from damaged microorganelles or proteins resulting from digestion in lysosomes. Additionally, autophagy is necessary to maintain homeostasis during cellular growth, development, and differentiation, and to protect cells from nutritional deficiencies or factors related to metabolism inhibition. Induced autophagy by various environmental factors has a dual role: it facilitates cellular survival in normal conditions, but the cascade of cellular death is accelerated by over-activated autophagy. Therefore, cellular death by autophagy has been known as programmed cell death type II. Autophagy causes or inhibits cellular death via the other mechanism, apoptosis, which is programmed cell death type I. Recently, it has been reported that autophagy increases in placenta-related obstetrical diseases such as preeclampsia and intrauterine growth retardation, although the mechanisms are still unclear. In particular, abnormal autophagic mechanisms prevent trophoblast invasion and inhibit trophoblast functions. Therefore, the objectives of this review are to examine the characteristics and functions of autophagy and to investigate the role of autophagy in the placenta and the trophoblast as a regulator of cell death.
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Affiliation(s)
- Jin-Sung Gong
- Department of Biomedical Science, CHA University, Seoul, Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seoul, Korea. ; CHA Placenta Institute, CHA University, Seoul, Korea
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Hsu KF, Pan HA, Hsu YY, Wu CM, Chung WJ, Huang SC. Enhanced myometrial autophagy in postpartum uterine involution. Taiwan J Obstet Gynecol 2014; 53:293-302. [PMID: 25286780 DOI: 10.1016/j.tjog.2013.01.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2013] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To understand the mechanisms of postpartum uterine involution, we investigated the uterine myometrial changes during pregnancy and the postpartum period. MATERIALS AND METHODS Nine groups of uterine myometrial samples from mice (n = 4) were collected on gestational Day 0 (nonpregnant), Day 1, Day 2, Day 7, Day 14, and Day 21 and on postpartum Day 1, Day 2, and Day 7. Human samples of uterine myometrium on term (n = 1) and postpartum Day 1 (n = 2) were also collected. Ki-67 immunostaining was used to determine myometrial proliferation. For cell hypertrophy analysis, organelle proteins, β-actin, prohibin, calnexin, and golgin-97 were analyzed by Western blotting. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and evaluation of activated caspase-3 expression by Western blot analysis assay were used to detect apoptosis. Autophagy was assayed via the evaluation of LC3 expression by Western blotting, immunohistochemistry, and autophagosomes by electron microscopy. RESULTS Uterine myocytes proliferated during the early stage of gestation with a peak at Day 2, whereas myocyte hypertrophy with increased cellular organelle production occurred gradually in later stages of pregnancy. Postpartum autophagy developed abruptly in uterine myocytes without obvious apoptosis. CONCLUSION Autophagy of myocytes may play an important role in uterine involution. These results have implications for our understanding of myometrial functional adaptations during pregnancy and the physiological role of autophagy in the uterine remodeling events in the postpartum period.
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Affiliation(s)
- Keng-Fu Hsu
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsien-An Pan
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Yun Hsu
- Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Ming Wu
- Department of Cell Biology and Anatomy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Ju Chung
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Oral Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Soon-Cen Huang
- Department of Obstetrics and Gynecology, Chi Mei Medical Center, Liouying, Tainan, Taiwan; Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Li H, Li Y, Morin D, Plymate S, Lye S, Dong X. The androgen receptor mediates antiapoptotic function in myometrial cells. Cell Death Dis 2014; 5:e1338. [PMID: 25032861 PMCID: PMC4123094 DOI: 10.1038/cddis.2014.303] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 06/06/2014] [Accepted: 06/11/2014] [Indexed: 01/11/2023]
Abstract
During pregnancy, myometrial phenotype is programmed into three characteristic stages referred to as the early proliferative, the midterm hypertrophic, and the late contractile stage. Increased myometrial growth in the early and midterm of pregnancy involves a complex process of cell proliferation, antiapoptosis and differentiation. We have previously demonstrated that the androgen receptor (AR) is required for myometrial cell proliferation by modulating IGF-1 signaling during early pregnancy. Here, we report that AR also exerts its antiapoptotic function in human myometrial cells. Enhanced AR expression protects, whereas AR silencing sensitizes myometrial cells to both intrinsic and extrinsic apoptotic stimuli. AR agonist inhibits, whereas AR antagonist induces myometrial cells to undergo apoptotic cell death. Gene microarray analysis confirms that the central functions of AR in myometrial cells are to regulate cell cycling and apoptosis through three major gene groups involving the epidermal growth factor (EGF) signaling, RNA splicing and DNA repair processes. AR mediates its antiapoptotic function through two distinct pathways. In the receptor-dependent pathway, AR is required for the expression of several protein factors within the EGF signaling pathway. Through the PI3K/Akt pathway, AR enhances the expression of the antiapoptotic protein Mcl-1. In the ligand-dependent pathway, AR agonist triggers the activation of Src kinase, which in turn phosphorylates STAT3 to increase Mcl-1 expression. We conclude from these results that the AR signaling exerts antiapoptotic function in myometrial cells, further supporting its key role in programming of myometrial phenotype.
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Affiliation(s)
- H Li
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Y Li
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - D Morin
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - S Plymate
- Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, Washington, USA
| | - S Lye
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
| | - X Dong
- 1] The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada [2] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
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Choi S, Shin H, Song H, Lim HJ. Suppression of autophagic activation in the mouse uterus by estrogen and progesterone. J Endocrinol 2014; 221:39-50. [PMID: 24443716 DOI: 10.1530/joe-13-0449] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Autophagy is a major cellular catabolic pathway tightly associated with cell survival. The involvement of autophagy in the prolonged survival of blastocysts in the uterus is well established, and it was assumed that ovarian steroid hormones - progesterone (P4) and estrogens - have important roles in the regulation of autophagy. However, information is scarce regarding whether these hormones regulate autophagy in certain hormone-responsive cellular systems. In this study, we investigated the effects of estrogen and P4 on autophagic response in the uteri of pregnant mice and in ovariectomized (OVX) mice treated with hormones. During pregnancy, autophagic response is high on days 1 and 2 when the uterus shows an inflammatory response to mating, but it subsides around the time of implantation. Dexamethasone treatment to day 1 pregnant mice reduced autophagy in the uterus. In OVX mouse uteri, estrogen or P4 reduces autophagic response within 6 h. Glycogen content in OVX uteri was increased by 3-methyladenine treatment, suggesting that autophagy is involved in glycogen breakdown in the hormone-deprived uterus. The classical nuclear receptor antagonists, ICI 182 780 or mifepristone, lead to the recovery of the autophagic response in OVX uteri. The suppression of autophagy by 17β-estradiol is inversely correlated with the accumulation of phospho-mouse target of rapamycin, and rapamycin treatment is moderately effective in the upregulation of autophagic response in OVX mouse uteri. Collectively, this study establishes that the uterine autophagy is induced in hormone-derived environment and is suppressed by hormone treatment. Uterine autophagy may have multiple functions as a responsive mechanism to acute inflammation and as an energy provider by breaking down glycogen under hormone deprivation.
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Affiliation(s)
- Soyoung Choi
- Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Korea Department of Biomedical Science, College of Life Science, CHA University, Seoul 135-081, Korea
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31
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Foster HA, Davies J, Pink RC, Turkcigdem S, Goumenou A, Carter DR, Saunders NJ, Thomas P, Karteris E. The human myometrium differentially expresses mTOR signalling components before and during pregnancy: evidence for regulation by progesterone. J Steroid Biochem Mol Biol 2014; 139:166-72. [PMID: 23541542 PMCID: PMC3855612 DOI: 10.1016/j.jsbmb.2013.02.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 02/07/2013] [Accepted: 02/24/2013] [Indexed: 10/27/2022]
Abstract
Emerging studies implicate the signalling of the mammalian target of rapamycin (mTOR) in a number of reproductive functions. To this date, there are no data regarding the expression of mTOR signalling components in the human myometrium during pregnancy. We hypothesized that mTOR-related genes might be differentially expressed in term or preterm labour as well as in labour or non-labour myometria during pregnancy. Using quantitative RT-PCR we demonstrate for first time that there is a significant downregulation of mTOR, DEPTOR, and Raptor in preterm labouring myometria when compared to non-pregnant tissues taken from the same area (lower segment). We used an immortalized myometrial cell line (ULTR) as an in vitro model to dissect further mTOR signalling. In ULTR cells DEPTOR and Rictor had a cytoplasmic distribution, whereas mTOR and Raptor were detected in the cytoplasm and the nucleus, indicative of mTORC1 shuttling. Treatment with inflammatory cytokines caused only minor changes in gene expression of these components, whereas progesterone caused significant down-regulation. We performed a non-biased gene expression analysis of ULTR cells using Nimblegen human gene expression microarray (n=3), and selected genes were validated by quantitative RT-PCR in progesterone treated myometrial cells. Progesterone significantly down-regulated key components of the mTOR pathway. We conclude that the human myometrium differentially expresses mTOR signalling components and they can be regulated by progesterone. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.
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Affiliation(s)
- Helen A Foster
- Biosciences, Centre for Cell and Chromosome Biology, Brunel University, Uxbridge UB8 3PH, UK
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Kyathanahalli C, Marks J, Nye K, Lao B, Albrecht ED, Aberdeen GW, Nathanielsz PW, Jeyasuria P, Condon JC. Cross-species withdrawal of MCL1 facilitates postpartum uterine involution in both the mouse and baboon. Endocrinology 2013; 154:4873-84. [PMID: 24140717 PMCID: PMC3836074 DOI: 10.1210/en.2013-1325] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A successful postpartum involution permits the postnatal uterus to rapidly regain its prepregnancy function and size to ultimately facilitate an ensuing blastocyst implantation. This study investigates the molecular mechanisms that govern the initiation of the involution process by examining the signaling events that occur as the uterus transitions from the pregnant to postnatal state. Using mouse and baboon uteri, we found a remarkable cross-species conservation at the signal transduction level as the pregnant uterus initiates and progresses through the involution process. This study originated with the observation of elevated levels of caspase-3 activation in both the laboring mouse and baboon uterus, which we found to be apoptotic in nature as evidenced by the concurrent appearance of cleaved poly(ADP-ribose) polymerase. We previously defined a nonapoptotic and potential tocolytic role for uterine caspase-3 during pregnancy regulated by increased antiapoptotic signaling mediated by myeloid cell leukemia sequence 1 and X-linked inhibitor of apoptosis. In contrast, this study determined that diminished antiapoptotic signaling in the postpartum uterus allowed for both endometrial apoptotic and myometrial autophagic episodes, which we speculate are responsible for the rapid reduction in size of the postpartum uterus. Using our human telomerase immortalized myometrial cell line and the Simian virus-40 immortalized endometrial cell line (12Z), we demonstrated that the withdrawal of antiapoptotic signaling was also an upstream event for both the autophagic and apoptotic processes in the human uterine myocyte and endometrial epithelial cell.
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Tal R, Segars JH. The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy. Hum Reprod Update 2013; 20:194-216. [PMID: 24077979 DOI: 10.1093/humupd/dmt042] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. METHODS Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. RESULTS Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. CONCLUSIONS Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess the potential of anti-angiogenic treatment strategies for uterine fibroids.
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Affiliation(s)
- Reshef Tal
- Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY 11219, USA
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KOIKE NATSUKI, TSUNEMI TAIHEI, UEKURI CHIHARU, AKASAKA JURIA, ITO FUMINORI, SHIGEMITSU AIKO, KOBAYASHI HIROSHI. Pathogenesis and malignant transformation of adenomyosis (Review). Oncol Rep 2012; 29:861-7. [DOI: 10.3892/or.2012.2184] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 10/02/2012] [Indexed: 11/06/2022] Open
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Xie N, Liu L, Li Y, Yu C, Lam S, Shynlova O, Gleave M, Challis JRG, Lye S, Dong X. Expression and function of myometrial PSF suggest a role in progesterone withdrawal and the initiation of labor. Mol Endocrinol 2012; 26:1370-9. [PMID: 22669741 DOI: 10.1210/me.2012-1088] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Progesterone (P4), acting through its receptor (PR), is essential for the maintenance of pregnancy. P4 acts by suppressing uterine contractility and the expression of contraction-associated proteins (CAP) such as connexin 43 (Cx43). P4 levels must be reduced or its actions blocked to allow the increased expression of CAP genes and the initiation of labor. Although the importance of progesterone in pregnancy has been known for about 80 yr, the fundamental mechanisms by which P4/PR maintains myometrial quiescence and by which this signaling is blocked at term labor remain to be determined. In this manuscript, we demonstrate that ligand-bound PR interacts with the Cx43 gene promoter through activator protein-1 transcription factors. We show that the ability of PR to repress Cx43 transcription is conferred through the recruitment of the PR coregulator, polypyrimidine tract binding protein-associated splicing factor (PSF), and the further recruitment of the yeast switch independent 3 homolog A/histone deacetylase corepressor complex. PSF expression is elevated during pregnancy but falls toward term as a result of increased mechanical stretch of the myometrium and a rise in the concentrations of circulating estrogen. These data together indicate that PSF is a critical regulator of P4/PR signaling and labor. We suggest that decreased PSF at term may result in a de-repression of PR transcriptional control of CAP genes and thereby contributes to a functional withdrawal of progesterone at term labor.
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Affiliation(s)
- Ning Xie
- Vancouver Prostate Center, Department of Urologic Sciences, University of British Columbia, Vancouver Canada
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White BG, MacPhee DJ. Distension of the uterus induces HspB1 expression in rat uterine smooth muscle. Am J Physiol Regul Integr Comp Physiol 2011; 301:R1418-26. [DOI: 10.1152/ajpregu.00272.2011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The uterine musculature, or myometrium, demonstrates tremendous plasticity during pregnancy under the influences of the endocrine environment and mechanical stresses. Expression of the small stress protein heat shock protein B1 (HspB1) has been reported to increase dramatically during late pregnancy, a period marked by myometrial hypertrophy caused by fetal growth-induced uterine distension. Thus, using unilaterally pregnant rat models and ovariectomized nonpregnant rats with uteri containing laminaria tents to induce uterine distension, we examined the effect of uterine distension on myometrial HspB1 expression. In unilaterally pregnant rats, HspB1 mRNA and Ser15-phosphorylated HspB1 (pSer15 HspB1) protein expression were significantly elevated in distended gravid uterine horns at days 19 and 23 (labor) of gestation compared with nongravid horns. Similarly, pSer15 HspB1 protein in situ was only readily detectable in the distended horns compared with the nongravid horns at days 19 and 23; however, pSer15 HspB1 was primarily detectable in situ at day 19 in membrane-associated regions, while it had primarily a cytoplasmic localization in myometrial cells at day 23. HspB1 mRNA and pSer15 HspB1 protein expression were also markedly increased in ovariectomized nonpregnant rat myometrium distended for 24 h with laminaria tents compared with empty horns. Therefore, uterine distension plays a major role in the stimulation of myometrial HspB1 expression, and increased expression of this small stress protein could be a mechanoadaptive response to the increasing uterine distension that occurs during pregnancy.
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Affiliation(s)
- B. G. White
- Division of Biomedical Sciences, Health Sciences Centre, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - D. J. MacPhee
- Division of Biomedical Sciences, Health Sciences Centre, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
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Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice. Proc Natl Acad Sci U S A 2011; 108:18073-8. [PMID: 22025690 DOI: 10.1073/pnas.1108180108] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Although preterm delivery is a major global health issue, its causes and underlying mechanism remain elusive. Using mutant mice, mimicking aspects of human preterm birth, we show here that uterine decidual senescence early in pregnancy via heightened mammalian target of rapamycin complex 1 (mTORC1) signaling is a significant contributor of preterm birth and fetal death, and that these adverse phenotypes are rescued by a low dose of rapamycin, an inhibitor of mTORC1 signaling. This role of mTORC1 signaling in determining the timing of birth in mice may help us better understand the mechanism of the timing of birth in humans and develop new and improved strategies to combat the global problem of preterm birth.
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Ciarmela P, Islam MS, Reis FM, Gray PC, Bloise E, Petraglia F, Vale W, Castellucci M. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update 2011; 17:772-90. [PMID: 21788281 DOI: 10.1093/humupd/dmr031] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women. METHODS For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed. RESULTS Different growth factors such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-β perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma. CONCLUSIONS Growth factors play an important role in the mechanisms involved in myometrial patho-physiology.
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Affiliation(s)
- Pasquapina Ciarmela
- Department of Experimental and Clinical Medicine, Faculty of Medicine, Polytechnic University of Marche, via Tronto 10/a, 60020 Ancona, Italy.
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Bodoor K, Lontay B, Safi R, Weitzel DH, Loiselle D, Wei Z, Lengyel S, McDonnell DP, Haystead TA. Smoothelin-like 1 protein is a bifunctional regulator of the progesterone receptor during pregnancy. J Biol Chem 2011; 286:31839-51. [PMID: 21771785 DOI: 10.1074/jbc.m111.270397] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
During pregnancy, uterine smooth muscle (USM) coordinately adapts its contractile phenotype in order to accommodate the developing fetus and then prepare for delivery. Herein we show that SMTNL1 plays a major role in pregnancy to promote adaptive responses in USM and that this process is specifically mediated through interactions of SMTNL1 with the steroid hormone receptor PR-B. In vitro and in vivo SMTNL1 selectively binds PR and not other steroid hormone receptors. The physiological relationship between the two proteins was also established in global gene expression and transcriptional reporter studies in pregnant smtnl1(-/-) mice and by RNA interference in progesterone-sensitive cell lines. We show that the contraction-associated and progestin-sensitive genes (oxytocin receptor, connexin 43, and cyclooxygenase-2) and prolactins are down-regulated in pregnant smtnl1(-/-) mice. We suggest that SMTNL1 is a bifunctional co-regulator of PR-B signaling and thus provides a molecular mechanism whereby PR-B is targeted to alter gene expression patterns within USM cells to coordinately promote alterations in USM function during pregnancy.
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Affiliation(s)
- Khaldon Bodoor
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
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Autophagy in term normal human placentas. Placenta 2011; 32:482-5. [DOI: 10.1016/j.placenta.2011.03.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Revised: 03/08/2011] [Accepted: 03/09/2011] [Indexed: 12/20/2022]
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Favaro RR, Salgado RM, Raspantini PR, Fortes ZB, Zorn TMT. Effects of long-term diabetes on the structure and cell proliferation of the myometrium in the early pregnancy of mice. Int J Exp Pathol 2010; 91:426-35. [PMID: 20586816 DOI: 10.1111/j.1365-2613.2010.00718.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
It is known that the development of diabetic complications in human pregnancy is directly related to the severity and the duration of this pathology. In this study, we developed a model of long-term type 1 diabetes to investigate its effects on the cytoarchitecture, extracellular matrix and cell proliferation during the first adaptation phase of the myometrium for pregnancy. A single dose of alloxan was used to induce diabetes in mice prior to pregnancy. To identify the temporal effects of diabetes the mice were divided into two groups: Group D1 (females that became pregnant 90-100 days after alloxan); Group D2 (females that became pregnant 100-110 days after alloxan). Uterine samples were collected after 168 h of pregnancy and processed for light and electron microscopy. In both groups the histomorphometric evaluation showed that diabetes promoted narrowing of the myometrial muscle layers which was correlated with decreased cell proliferation demonstrated by PCNA immunodetection. In D1, diabetes increased the distance between muscle layers and promoted oedema. Contrarily, in D2 the distance between muscle layers decreased and, instead of oedema, there was a markedly deposition of collagen in the myometrium. Ultrastructural analysis showed that diabetes affects the organization of the smooth muscle cells and their myofilaments. Consistently, the immunoreaction for smooth muscle α-actin revealed clear disorganization of the contractile apparatus in both diabetic groups. In conclusion, the present model demonstrated that long-term diabetes promotes significant alterations in the myometrium in a time-sensitive manner. Together, these alterations indicate that diabetes impairs the first phenotypic adaptation phase of the pregnant myometrium.
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Affiliation(s)
- Rodolfo R Favaro
- Laboratory of Reproductive and Extracellular Matrix Biology, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
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Pöllänen E, Ronkainen PHA, Horttanainen M, Takala T, Puolakka J, Suominen H, Sipilä S, Kovanen V. Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle. Growth Horm IGF Res 2010; 20:372-379. [PMID: 20724185 DOI: 10.1016/j.ghir.2010.07.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Revised: 06/30/2010] [Accepted: 07/21/2010] [Indexed: 01/14/2023]
Abstract
OBJECTIVES To investigate the effects of combined hormone replacement therapy (HRT) and its effective agents on the IGF-1 signaling pathway. DESIGN AND METHODS To examine the effects of HRT on skeletal muscle in vivo, we utilized pre- and post-intervention samples from a randomized double blinded trial with 50-57-year-old women. The intervention included the year-long use of either HRT preparation (2 mg 17β-estradiol, E₂; 1mg norethisterone acetate, NETA, n=10) or placebo (CO, n=9). Microarray technology and quantitative PCR (qPCR) were used to study the expression of insulin-like growth factor I (IGF-1) and its splice variants as well as IGF-1 receptor, Akt1, mTOR, FOXO1, FOXO3, atrogin, estrogen receptors and androgen receptor in muscle samples. Serum concentrations of IGF-1, E(2) and testosterone were measured. C2C12 myotubes were fed with E₂ or NETA followed by analyzing the expression of essentially the same gene transcripts as in human samples by qPCR and phosphorylation of Akt and mTOR by Western blotting. RESULTS The gene expression of IGF-1 and its splice variant, IGF-1Ec (also known as the mechano growth factor or MGF), mTOR, FOXO3, and AR was up-regulated among the HRT users compared to the CO (P<0.05), while Akt1 was down-regulated (P<0.05). The change in the level of IGF-1Ec transcript correlated positively with muscle size at post-intervention (r=0.5, P<0.05). In C2C12 myotubes, no statistically significant effects of either E₂ or NETA at the level of gene transcripts studied were identified. The amount of phosphorylated Akt appeared to respond to NETA, albeit the response was not statistically significant. Phosphorylation of mTOR did not respond to either of the treatments. CONCLUSION Year-long postmenopausal HRT was found to affect the expression of the genes along the IGF-1 signaling cascade reflecting the higher muscle mass compared to the CO women. By using cell culture model we were, however, unable to confirm the possible differential role of E₂ and NETA. It appears that the synchronous presence of both effective agents of the HRT or the presence of yet unidentified microenvironmental factors providing proper paracrine signals naturally existing in the intact muscle tissue is critical for appropriate signaling via sex steroid-IGF-1 axis to occur.
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MESH Headings
- Estradiol/blood
- Estradiol/therapeutic use
- Estrogen Replacement Therapy
- Female
- Forkhead Box Protein O1
- Forkhead Box Protein O3
- Forkhead Transcription Factors/biosynthesis
- Forkhead Transcription Factors/genetics
- Humans
- Insulin-Like Growth Factor I/analysis
- Insulin-Like Growth Factor I/biosynthesis
- Insulin-Like Growth Factor I/genetics
- Middle Aged
- Muscle Fibers, Skeletal/chemistry
- Muscle Fibers, Skeletal/drug effects
- Muscle Proteins/biosynthesis
- Muscle Proteins/genetics
- Muscle, Skeletal/chemistry
- Muscle, Skeletal/drug effects
- Norethindrone/analogs & derivatives
- Norethindrone/therapeutic use
- Norethindrone Acetate
- Protein Isoforms/biosynthesis
- Protein Isoforms/genetics
- Proto-Oncogene Proteins c-akt/biosynthesis
- Proto-Oncogene Proteins c-akt/genetics
- Randomized Controlled Trials as Topic
- Receptor, IGF Type 1/biosynthesis
- Receptor, IGF Type 1/genetics
- Receptors, Androgen/biosynthesis
- Receptors, Androgen/genetics
- Receptors, Estrogen/biosynthesis
- Receptors, Estrogen/genetics
- SKP Cullin F-Box Protein Ligases/biosynthesis
- SKP Cullin F-Box Protein Ligases/genetics
- TOR Serine-Threonine Kinases/biosynthesis
- TOR Serine-Threonine Kinases/genetics
- Testosterone/blood
- Transcription, Genetic/drug effects
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Affiliation(s)
- Eija Pöllänen
- Gerontology Research Centre, University of Jyväskylä, P.O. Box 35, FIN-40014 University of Jyväskylä, Jyväskylä, Finland
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Shynlova O, Kwong R, Lye SJ. Mechanical stretch regulates hypertrophic phenotype of the myometrium during pregnancy. Reproduction 2010; 139:247-53. [PMID: 19776098 DOI: 10.1530/rep-09-0260] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The adaptive growth of the uterus is a critical event that involves changes in cellular phenotypes throughout pregnancy. In early pregnancy, uterine growth is due to hyperplasia of uterine smooth muscle cells (SMCs) within the myometrium; however, the major component of myometrial growth occurs after mid-gestation. This study sought to test the hypothesis that increase in myometrial growth seen during late pregnancy is due to SMC hypertrophy caused by mechanical stretch of uterine tissue by a growing fetus(es) by providing direct measurements of individual SMC size. We employed a stereological approach to calculate the average cell volumes of uterine myocytes through diameter measurements using the Stereoinvestigator statistical software. Uterine tissues were collected from nonpregnant Wistar rats, as well as from gravid and nongravid horns of unilaterally pregnant animals on gestational days (d) 8 (early gestation), 14 (mid-gestation), 19 (late gestation), 22 (term), and 4 days post partum. Anti-caveolin-1 immunostaining was used to clearly delineate SMC boundaries. The stereological analysis revealed that the dramatic increase in myometrial growth seen during late gestation (d19-22) is due to a threefold increase in the size of uterine myocytes. A significant increase in SMC volumes was detected in the gravid uterine horn as compared with the corresponding empty horn of unilateral term pregnant animals (day 22, mean cell volume 1114 vs 361 microm(3), P<0.05), indicating the effect of uterine occupancy. The restriction of the hypertrophy to cells within the gravid horn suggests that it may be a response to the biological mechanical stretch of uterine walls by the growing fetus(es) and placenta(s).
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Affiliation(s)
- Oksana Shynlova
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 25 Orde Street, Room 6-1019, Toronto, Ontario, Canada.
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