Targeted proteins for vaginal epithelial repair

Excerpt:


J. Pharm. Pharmacogn. Res., vol. 11, no. 1, pp. 110-116, January-February 2023. DOI: https://doi.org/10.56499/jppres22.1512_11.1.110 Original Article Epithelial thinning in vaginal atrophy related to lowering of calcitonin gene-related protein, vascular endothelial growth factor, and nerve growth factor expressions in a menopausal rat model [Adelgazamiento epitelial en la atrofia vaginal relacionado con la disminución de las expresiones de … Continue reading Targeted proteins for vaginal epithelial repair

J. Pharm. Pharmacogn. Res., vol. 11, no. 1, pp. 110-116, January-February 2023.

DOI: https://doi.org/10.56499/jppres22.1512_11.1.110

Original Article

Epithelial thinning in vaginal atrophy related to lowering of calcitonin gene-related protein, vascular endothelial growth factor, and nerve growth factor expressions in a menopausal rat model

[Adelgazamiento epitelial en la atrofia vaginal relacionado con la disminución de las expresiones de la proteína relacionada con el gen de la calcitonina, el factor de crecimiento endotelial vascular y el factor de crecimiento nervioso en un modelo de rata menopáusica]

An Nisa Fithri1,2*, Yuyun Yueniwati3, I Wayan Arsana4, Husnul Khotimah5, Wiwit Nurwidyaningtyas6

1Doctoral Program of Medical Sciences, Faculty of Medicine, Universitas Brawijaya, Indonesia.

2Midwifery Program, Sekolah Tinggi Ilmu Kesehatan Kendedes Malang, 65126, Indonesia.

3Department of Radiology, Public Saiful Anwar Hospital, Malang, Indonesia,

4Department of Fertility, Endocrinology and Reproduction, Obstetric and Gynecology Laboratory, Public Saiful Anwar Hospital, Faculty of Medicine, Universitas Brawijaya, Indonesia.

5Department of Pharmacology, Universitas Brawijaya, Indonesia.

6Department Molecular and Cellular Biology, Sekolah Tinggi Ilmu Kesehatan Kendedes, Malang, 65126, Indonesia.

*E-mail: teh.nisa1@gmail.com

Abstract

Context: Vaginal atrophy has been observed as a common sexual problem in post-menopausal women. The targeted protein to counteract menopause problems related to vaginal epithelial thinning is currently a research problem that has not been fully investigated.

Aims: To explore the possible mechanism underlying vaginal atrophy in rat models.

Methods: Following three-week ovariectomy (OVX), Sprague-Dawley female rats were randomly divided into two groups and orally administered estradiol for two weeks in the treated group. In parallel with this, six rats with sham surgery were used as control. Marker-related vaginal atrophy, including calcitonin gene-related protein (CGRP), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF) in the vaginal wall, were compared using immunohistochemistry.

Results: OVX as a menopausal model significantly induced vaginal epithelial cell thinning and decreased the expression of CGRP, VEGF, and NGF compared with sham surgery animals (p<0.05). Estrogen replacement in OVX rats reversed the vaginal atrophic by recovering the protein expression CGRP, VEGF, and NGF (p<0.05).

Conclusions: Thus, it may be concluded that a possible mechanism underlying the OVX-induced vaginal atrophy may be related to the downregulation expression of CGRP, VEGF, and NGF in vaginal tissue.

Keywords: calcitonin gene-related protein; menopause; nerve growth factor; ovariectomy model; vaginal atrophy; vascular endothelial growth factor.

Resumen

Contexto: Se ha observado que la atrofia vaginal es un problema sexual común en las mujeres posmenopáusicas. La proteína dirigida a contrarrestar los problemas de la menopausia relacionados con el adelgazamiento del epitelio vaginal es actualmente un problema de investigación que no se ha investigado completamente.

Objetivos: Explorar el posible mecanismo subyacente a la atrofia vaginal en modelos de rata.

Métodos: Tras una ovariectomía (OVX) de tres semanas, se dividieron aleatoriamente ratas hembras Sprague-Dawley en dos grupos y se les administró estradiol por vía oral durante dos semanas en el grupo tratado. Paralelamente, se utilizaron como control seis ratas con cirugía simulada. Se compararon mediante inmunohistoquímica los marcadores de atrofia vaginal, como la proteína relacionada con el gen de la calcitonina (CGRP), el factor de crecimiento endotelial vascular (VEGF) y el factor de crecimiento nervioso (NGF) en la pared vaginal.

Resultados: La OVX como modelo menopáusico indujo significativamente el adelgazamiento de las células epiteliales vaginales y disminuyó la expresión de CGRP, VEGF y NGF en comparación con los animales sometidos a cirugía simulada (p<0,05). El reemplazo de estrógenos en las ratas OVX revirtió la atrofia vaginal recuperando la expresión de proteínas CGRP, VEGF y NGF (p<0,05).

Conclusiones: Por lo tanto, se puede concluir que un posible mecanismo subyacente a la atrofia vaginal inducida por la OVX puede estar relacionado con la disminución de la expresión de CGRP, VEGF y NGF en el tejido vaginal.

Palabras Clave: atrofia vaginal; factor de crecimiento endotelial vascular; factor de crecimiento nervioso; ; menopausia; modelo de ovariectomía; proteína relacionada con el gen de la calcitonina.

Citation Format: Fithri AN, Yueniwati Y, Arsana IW, Khotimah H, Nurwidyaningtyas W (2023) Epithelial thinning in vaginal atrophy related to lowering of calcitonin gene-related protein, vascular endothelial growth factor, and nerve growth factor expressions in a menopausal rat model. J Pharm Pharmacogn Res 11(1): 110–116. https://doi.org/10.56499/jppres22.1512_11.1.110
References

Ali A, Syed SM, Jamaluddin M, Colino-Sanguino Y, Gallego-Ortega, D, Tanwar PS (2020) Cell lineage tracing identifies hormone-regulated and Wnt-responsive vaginal epithelial stem cells. Cell Rep 30(5): 1463–1477.e7. https://doi.org/10.1016/j.celrep.2020.01.003

Armayanti LY, Wulansari NT (2020) Regulation of sex steroid sex hormones on calcitonin gene-related peptide (CGRP)’s mRNA expression in vaginal mucosa epitel of bilateral ovarectomized Wistar rats. Biomed Pharmacol J 13(1): 263–268. https://dx.doi.org/10.13005/bpj/1885

Bleibel B, Nguyen H (2022) Vaginal Atrophy. [Updated 2022 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559297/

Chow C, Che S, Qin HY, Kwan HY, Bian ZX, Wong H (2019) From psychology to physicality: How nerve growth factor transduces early life stress into gastrointestinal motility disorders later in life. Cell Cycle 18(16): 1824–1829. https://doi.org/10.1080/15384101.2019.1637203

Cora MC, Kooistra L, Travlos G (2015) Vaginal cytology of the laboratory rat and mouse: Review and criteria for the staging of the estrous cycle using stained vaginal smears. Toxicol Pathol 43: 776–793. https://doi.org/10.1177/0192623315570339

Dos Santos CCM, Uggioni MLR, Colonetti T, Colonetti L, Grande AJ, Da Rosa MI (2021) Hyaluronic acid in postmenopause vaginal atrophy: A systematic review. J Sex Med 18(1): 156–166. https://doi.org/10.1016/j.jsxm.2020.10.016

Edwards D, Panay N (2016) Treating vulvovaginal atrophy/genitourinary syndrome of menopause: How important is vaginal lubricant and moisturizer composition? Climacteric 19(2): 151–161. https://doi.org/10.3109/13697137.2015.1124259

Gao H, Xiao M, Bai H, Zhang Z (2017) Sexual function and quality of life among patients with endometrial cancer after surgery. Int J Gynecol Cancer 27(3): 608–612. https://doi.org/10.1097/IGC.0000000000000905

Geller EJ, Bretschneider CE, Wu JM, Kenton K, Matthews CA (2021) Sexual function after minimally invasive total hysterectomy and sacrocolpopexy. J Minim Invasive Gynecol 28(9): 1603–1609. https://doi.org/10.1016/j.jmig.2021.01.021

Handy AB, Meston CM (2021) An objective measure of vaginal lubrication in women with and without sexual arousal concerns. J Sex Marital Ther 47(1): 32–42. https://doi.org/10.1080/0092623X.2020.1801542

Isaza PG (2019) Use of growth factors for vulvo/vaginal bio-stimulation. Surg Technol Int 15(34): 269–273.

Karppinen JE, Törmäkangas T, Kujala UM, Sipilä S, Laukkanen J, Aukee P, Kovanen V, Laakkonen EK (2022) Menopause modulates the circulating metabolome: evidence from a prospective cohort study. Eur J Prev Cardiol 29(10): 1448–1459. https://doi.org/10.1093/eurjpc/zwac060

Kasap B, Kasap Ş Vatansever S, Kendirci R, Yılmaz O, Ćaşlır M, Edgṻnlṻ T, Akın MN (2019) Effects of adipose and bone marrow-derived mesenchymal stem cells on vaginal atrophy in a rat menopause model. Gene 711: 143937. https://doi.org/10.1016/j.gene.2019.06.027

Laumann EO, Paik A, Rosen RC (1999) Sexual dysfunction in the United States: Prevalence and predictors. JAMA 281(6): 537–544. https://doi.org/10.1001/jama.281.6.537

Li S, Herrera GG, Tam KK, Lizarraga JS, Beedle MT, Winuthayanon W (2018) Estrogen action in the epithelial cells of the mouse vagina regulates neutrophil infiltration and vaginal tissue integrity. Sci Rep 8(1): 11247. https://doi.org/10.1038/s41598-018-29423-5

Liu H, Zhong L, Zhang Y, Liu X, Li J (2018) Rutin attenuates cerebral ischemia-reperfusion injury in ovariectomized rats via estrogen-receptor-mediated BDNF-TrkB and NGF-TrkA signaling. Biochem Cell Biol 96(5): 672–681. https://doi.org/10.1139/bcb-2017-0209

Molnár I (2020) Interactions among thyroid hormone (FT4), chemokine (MCP-1) and neurotrophin (NGF-β) levels studied in Hungarian post-menopausal and obese women. Cytokine 127: 154948. https://doi.org/10.1016/j.cyto.2019.154948

Mueck AO, Ruan X, Prasauskas V, Grob P, Ortmann O (2018) Treatment of vaginal atrophy with estriol and Lactobacilli combination: A clinical review. Climateric 21(2): 140–147. https://doi.org/10.1080/13697137.2017.1421923

Nakamura T, Miyagawa S, Katsu Y, Sato T, Iguchi T, Ohta Y (2012) Sequential changes in the expression of Wnt- and Notch-related genes in the vagina and uterus of ovariectomized mice after estrogen exposure. In Vivo 26(6): 899-906.

Nappi R, Martini E, Cucinella L, Martella S, Tiranini L, Inzoli A, Brambilla E, Bosoni D, Cassani C, Gardella B (2019) Addressing vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) for healthy aging in women. Front Endocrinol 10: 561. https://doi.org/10.3389/fendo.2019.00561

Naumova I, Castelo-Branco C (2018) Current treatment options for post-menopausal vaginal atrophy. Int J Womens Health 10: 387–395. https://doi.org/10.2147/IJWH.S158913

Oliveira MA, Lima WG, Schettini DA, Tilelli CQ, Chaves VE (2019) Is calcitonin gene-related peptide a modulator of menopausal vasomotor symptoms? Endocrine 63(2): 193–203. https://doi.org/10.1007/s12020-018-1777-z

Palacios S, Nappi R, Bruyniks N, Particco M, Panay N, EVES Study Investigators (2018) The European Vulvovaginal Epidemiological Survey (EVES): Prevalence, symptoms and impact of vulvovaginal atrophy of menopause. Climacteric 21(3): 286–291. https://doi.org/10.1080/13697137.2018.1446930

Pan Z, Wen S, Qiao X, Yang M, Shen X, Xu L (2022) Different regimens of menopausal hormone therapy for improving sleep quality: a systematic review and meta-analysis. Menopause 29(5): 627–635. https://doi.org/10.1097/GME.0000000000001945

Pérez-Herrezuelo I, Aibar-Almazán A, Martínez-Amat A, Fábrega-Cuadros R, Díaz-Mohedo E, Wangensteen R, Hita-Contreras F (2020) Female sexual function and its association with the severity of menopause-related symptoms. Int J Environ Res Public Health 17(19): 7235. https://doi.org/10.3390/ijerph17197235

Shafaat S, Mangir N, Chapple C, MacNeil S, Hearnden V (2022) A physiologically relevant, estradiol-17β[E2]-responsive in vitro tissue-engineered model of the vaginal epithelium for vaginal tissue research. Neurourol Urodyn 41(4): 905–917. https://doi.org/10.1002/nau.24908

Shang X, Zhang L, Jin R, Yang H, Tao H (2021) Estrogen regulation of the expression of pain factor NGF in rat chondrocytes. J Pain Res 9(14): 931–940. https://doi.org/10.2147/JPR.S297442

Shen Z, Fahey JV, Bodwell JE, Rodriguez-Garcia M, Rossoll RM, Crist SG, Patel MV, Wira CR (2013) Estradiol regulation of nucleotidases in female reproductive tract epithelial cells and fibroblasts. PLoS One 8(7): e69854. https://doi.org/10.1371/journal.pone.0069854

Tsai T, Yeh C, Hwang T (2011) Female sexual dysfunction: physiology, epidemiology, classification, evaluation and treatment. Urol Sci 22(1): 7–13. https://doi.org/10.1016/S1879-5226(11)60002-X

Winuthayanon W, Lierz SL, Delarosa KC, Sampels SR, Donoghue LJ, Hewitt SC, Korach KS (2017) Juxtacrine activity of estrogen receptor α in uterine stromal cells is necessary for estrogen-induced epithelial cell proliferation. Sci Rep 7(1): 8377. https://doi.org/10.1038/s41598-017-07728-1

Yin QZ, Lu H, Li LM, Yie SM, Hu X, Liu ZB, Zheng X, Cao S, Yao ZY (2013) Impacts of You Gui Wan on the expression of estrogen receptors and angiogenic factors in OVX‑rat vagina: A possible mechanism for the trophic effect of the formula on OVX‑induced vaginal atrophy. Mol Med Rep 8(5): 1329–1336. https://doi.org/10.3892/mmr.2013.1670

© 2023 Journal of Pharmacy & Pharmacognosy Research

Toxicity evaluation of Ruta angustifolia leaves ethanolic extract
J. Pharm. Pharmacogn. Res., vol. 11, no. 3, pp. 437-447, May-June 2023. DOI: https://doi.org/10.56499/jppres23.1609_11.3.437 Original Article Acute and repeated dose 28-day oral toxicity of Ruta angustifolia Pers. leaves ethanolic extract in Wistar rats [Toxicidad oral aguda y por dosis repetidas durante 28 días del extracto etanólico de hojas de Ruta angustifolia Pers. en ratas Wistar] Tutik … Continue reading Toxicity evaluation of Ruta angustifolia leaves ethanolic extract
Adolescents in Indonesia and COVID-19 pandemic
J. Pharm. Pharmacogn. Res., vol. 11, no. 3, pp. 426-436, May-June 2023. DOI: https://doi.org/10.56499/jppres22.1560_11.3.426 Original Article Perception, mental health, and social media exposure on adolescents in Indonesia during COVID-19 pandemic [Percepción, salud mental y exposición a los medios sociales en adolescentes de Indonesia durante la pandemia de COVID-19] Efa Nugroho1*, Alfiana Ainun Nisa1, Widya Hary Cahyati1, … Continue reading Adolescents in Indonesia and COVID-19 pandemic
Decaffeinated green tea and coffee extracts and metabolic syndrome
J. Pharm. Pharmacogn. Res., vol. 11, no. 3, pp. 414-425, May-June 2023. DOI: https://doi.org/10.56499/jppres23.1593_11.3.414 Original Article Decaffeinated green tea and green coffee extracts as metformin’s add-on enhance metabolic syndrome risk factors and improve the cardiac insulin-gene-related pathway [Extractos de té verde y café verde descafeinados como complemento de la metformina mejoran los factores de riesgo del … Continue reading Decaffeinated green tea and coffee extracts and metabolic syndrome

© 2013-2020 by the authors; licensee JPPRes, Antofagasta, Chile. This journal is an open-access journal distributed under the terms and conditions of the Creative Commons Attribution license-Non Commercial 4.0 international. The content on this site is intended for health professionals. If you are not a health professional, please talk to your doctor about any doubts or concerns regarding your health

Made with ♥ by AVAGAX Studio