Plasma Levels of Transforming Growth Factor-Beta 1 in Women with Pelvic Organ Prolapse

Abstract

Objective: In women with pelvic organ prolapse (POP), decreased expression of transforming growth factor-beta 1 (TGF-β1) has been shown in POP tissues. However, no studies have evaluated plasma TGF-β1 levels in patients with POP, so it is unknown whether they are also changed or not. Therefore, we compared plasma TGF-β1 levels in women with and without POP. Methods: Participants were 49 women with POP and 23 healthy control women. All participants were postmenopausal. We measured plasma TGF-β1 and compared data between patients with POP and controls, and between patients with uterine prolapse (UP, n = 19) and those with a cystocele (CC, n = 30). In addition, in patients, we assessed the POP quantification system (POP-Q) stage. Results: Plasma TGF-β1 levels were significantly lower in patients than in healthy controls. POP-Q stage was not significantly different between the UP and CC subgroups, but POP-Q stage IV was diagnosed in 63% of patients with UP and 7% of those with CC. Plasma TGF-β1 levels were significantly lower in the CC subgroup than in the UP subgroup. Conclusion: Plasma TGF-β1 is decreased in POP. It remains unclear whether the lower levels indicate a reduction in systemic TGF-β1 activity, but they can be assumed to reflect reduced TGF-β1 expression in POP tissues.

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Sugaya, K. , Kadekawa, K. , Ashitomi, K. , Nishijima, S. and Matsumoto, S. (2023) Plasma Levels of Transforming Growth Factor-Beta 1 in Women with Pelvic Organ Prolapse. Open Journal of Urology, 13, 133-142. doi: 10.4236/oju.2023.135017.

1. Introduction

Pelvic organ prolapse (POP) is characterized by the weakening of pelvic supportive tissue in women, which leads to prolapse of the uterus, bladder, and rectum outside the pelvis through the vagina [1] . POP, which is more common in older women, affects approximately 9% of women worldwide and greatly impacts their quality of life [2] [3] . A large community-based retrospective cohort study identified factors that increase the risk of POP, i.e. older age, postmenopausal status, higher parity, elevated intraabdominal pressure, and overweight [4] [5] [6] . In addition, a combination of support defects in the anterior, posterior, and apical vaginal segments and abnormalities of connective tissue structure or its repair mechanism might predispose women to develop POP [4] [5] [7] . Recent studies on POP have focused on the abnormal structure and organization of pelvic floor connective tissue and the molecular alterations in uterosacral ligaments [8] [9] [10] . Notably, a breakdown of the extracellular matrix is commonly reported [11] [12] , and this process was shown to decrease the strength of supportive structures and contribute to the pathogenesis of POP [13] [14] . However, the exact molecular mechanisms underlying the breakdown of the extracellular matrix are not yet fully understood.

The cytokine transforming growth factor-beta 1 (TGF-β1) remodels the extracellular matrix by regulating multiple enzymes and extracellular matrix components [15] . In women with POP, decreased expression of TGF-β1 has been shown in fibroblasts, the pubovaginal fascia, and cardinal ligament tissues [16] [17] [18] [19] [20] . The expression level of TGF-β1 is positively correlated with collagen expression [20] , so low levels of TGF-β1 expression might be associated with the occurrence of POP. To date, no studies have evaluated plasma TGF-β1 levels in patients with POP, so it is unknown whether they are also decreased. Therefore, this study compared plasma TGF-β1 levels in women with POP and healthy control women.

2. Participants and Methods

Participants (N = 72) were 49 female patients (49 - 85 years old) who were diagnosed with POP between December 1, 2011 and March 31, 2013, and 23 healthy female controls (49 - 75 years old). Patients were selected from women attending a consultation at the Department of Urology at Okinawa Kyodo Hospital for that period. POP and POP quantification system (POP-Q) stage [21] were diagnosed by cystography and pelvic examination, and patients were asked whether they had stress urinary incontinence. Inclusion criteria for the POP patient group included POP-Q stage 2 or greater prolapse, as assessed by a single physician (K.K), and a plan for surgery by the same physician to treat the symptomatic prolapse. Healthy controls were volunteers without urinary tract symptoms who were recruited from Kitakami Central Hospital staff (nurses, helpers, and clerks) and their families for the period between December 1, 2012 and March 31, 2013.

All participants were postmenopausal and had no other urological or gynecological illnesses, diabetes, or hypertension. In all participants, blood was drawn at study visits, outpatient visits, or on admission for surgery, and plasma TGF-β1 was measured by enzyme-linked immunosorbent assay (SRL, Inc., Tokyo, Japan). Height, body weight, and body mass index (BMI) were also measured. Data were compared between patients with POP and healthy controls and between patients with uterine prolapse (UP) and those with a cystocele (CC).

This was a multicenter clinical study. The study was approved by the ethics committee of Okinawa Kyodo Hospital on behalf of all participating institutions (approval No. 2010-005). Before enrollment, all participants were given a detailed explanation of the objectives and methods of the study and gave their written consent.

Results are expressed as the mean ± standard deviation (SD). The unpaired t test was used for statistical analysis, and the p-value of less than 0.05 was used as the threshold for significance.

3. Results

Although all participants were postmenopausal, the healthy controls were significantly younger than the patients (Table 1). They were also significantly taller, but body weight and BMI were not significantly different between the two groups. In healthy controls, plasma TGF-β1 levels did not correlate with age, height, weight, or BMI (Table 2). Plasma TGF-β1 levels were significantly (p = 0.027) lower in patients (6.3 ± 3.6 ng/mL) than in healthy controls (8.1 ± 5.7 ng/mL) (Figure 1).

Table 1. Basic characteristics of women with pelvic organ prolapse (POP) and healthy control women (Controls).

Table 2. Relationship between age, height, weight or BML (x) and plasma TGF-β1 levels (y) in healthy controls.

Figure 1. Comparison of plasma TGF-β1 levels between women with pelvic organ prolapse (POP, n = 49) and healthy control women (Controls, n = 23). Plasma TGF-β1 levels were significantly (p = 0.027) lower in POP patients (6.3 ± 3.6 ng/mL) than in healthy controls (8.1 ± 5.7 ng/mL) (Mean ± SD).

Figure 2. Comparison of plasma TGF-β1 levels between women with uterine prolapse (UP, n = 19) and those with a cystocele (CC, n = 30). Plasma TGF-β1 levels were significantly (p = 0.048) higher in the UP group (7.4 ± 4.3 ng/mL) than in the CC group (5.9 ± 3.6 ng/mL) (Mean ± SD).

Among the patients, 19 had UP and 30 CC. We found no significant differences in age, BMI, parity, and presence or absence of stress urinary incontinence between the two subgroups (Table 3). Although POP-Q stage was also not significantly different between the two subgroups, POP-Q stage IV was diagnosed in 63% of patients with UP but in only 7% of those with CC. Plasma TGF-β1 levels were significantly (p = 0.048) higher in the UP group (7.4 ± 4.3 ng/mL) than in the CC group (5.9 ± 3.6 ng/mL) (Figure 2).

Table 3. Basic characteristics of women with uterine prolapse (UP) and those with a cystocele (CC).

4. Discussion

The present study aimed to clarify whether plasma TGF-β1 levels are also decreased in POP patients, similar to TGF-β1 levels in POP tissues. Although the healthy controls were significantly younger than the patients, all participants were postmenopausal, and plasma TGF-β1 levels did not correlate with age, height, weight, or BMI in the healthy controls; consequently, it was determined that the healthy female volunteers were suitable as controls for patients [22] . Plasma TGF-β1 levels were significantly lower in patients than in healthy controls. This result is consistent with previous findings of reduced TGF-β1 expression in the pubovaginal fascia and cardinal ligament tissues of patients with POP [16] - [20] . Moreover, among the patients, plasma TGF-β1 levels were significantly lower in the CC group than in the UP group, indicating that plasma TGF-β1 levels might reflect TGF-β1 expression in the pelvis.

TGF-β1 is involved in the synthesis of the extracellular matrix and the inhibition of matrix metalloproteinases. Furthermore, sustained elevations of TGF-β1 have been associated with multiple other pathological conditions, such as pulmonary fibrosis, keloid formation, coronary artery restenosis, and acute respiratory distress syndrome [23] . Thus, although the molecular mechanism of TGF-β1 remains unclear, TGF-β1 expression is enhanced in conditions with increased fibrosis in tissue. Increased mechanical strain can reduce the expression of TGF-β1 [23] [24] , so it is understandable that both collagen and TGF-β1 expression are reduced in POP tissues [10] . However, TGF-β1 expression was reported to be increased in the fascia of inguinal hernias [25] and POP tissues of higher stage POP (POP-Q stage IV) but not lower stage POP (POP-Q stages II and III) [22] . These findings are interesting because both inguinal hernias and POP are associated with a loss of fascial support, so the pathophysiology of the two conditions might be similar [22] . In the present study, POP-Q stage IV was diagnosed in 63% of patients with UP and 7% of those with CC, and plasma TGF-β1 levels were significantly higher in the UP group than in the CC group; these results indicate that UP and CC may differ in the degree of TGF-β1 involvement in their disease progression.

Several diseases have been reported to be associated with elevated plasma TGF-β1, including schizophrenia [26] , astrocytoma [27] , open-angle glaucoma [28] , advanced or metastatic cancers [29] - [33] , chronic pancreatitis [34] , atrial fibrillation [35] and hypertension [36] [37] , and many of these diseases also show elevated TGF-β1 expression in the pathogenic tissues. However, we were unable to find any reports on diseases where plasma TGF-β1 is decreased, and the only study that found decreased plasma TGF-β1 was on physical exercise [38] . Hence, to the best of our knowledge this is the first report of a disease in which plasma TGF-β1 is decreased. The question whether decreased plasma TGF-β1 levels indicate a reduction in systemic TGF-β1 activity is unclear, but they can be assumed to reflect reduced TGF-β1 expression in POP tissues.

Angiotensin II subtypes 1 receptor antagonists and angiotensin-converting enzyme inhibitors inhibit TGF-β1 activity [36] . Tranilast, an anti-allergic agent and keloid treatment, also suppresses TGF-β1 activity [39] . Tranilast results in thinning of the bladder wall, causing interstitial cystitis-like symptoms [40] . Therefore, future studies may be able to evaluate whether these drugs affect the onset of POP by measuring plasma TGF-β1.

This study has some limitations. The number of controls was small, and age was significantly different between patients and controls, although all participants were postmenopausal. Future studies are needed to evaluate whether plasma TGF-β1 levels change with age. Moreover, because we did not compare TGF-β1 expression in POP tissues and plasma TGF-β1 levels, our findings are preliminary.

5. Conclusion

Plasma TGF-β1 levels are significantly lower in patients with POP than in healthy controls and significantly lower in patients with CC than in those with UP. It remains unclear whether the lower levels indicate a reduction in systemic TGF-β1 activity, but they can be assumed to reflect reduced TGF-β1 expression in POP tissues, especially in CC tissues. Future studies may be able to measure plasma TGF-β1 to investigate whether drugs affect connective tissue formation and the onset of POP.

Abbreviations

BMI: Body Mass Index;

CC: Cystocele;

POP: Pelvic organ Prolapse;

POP-Q: POP Quantification System;

SD: Standard Deviation;

TGF-β1: Transforming Growth Factor-Beta 1;

UP: Uterine Prolapsed.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

References

[1] Chung, S.H. and Kim, W.B. (2018) Various Approaches and Treatments for Pelvic Organ Prolapse in Women. Journal of Menopausal Medicine, 24, 155-162.
https://doi.org/10.6118/jmm.2018.24.3.155
[2] Vos, T., Flaxman, A.D., Naghavi, M., et al. (2012) Years Lived with Disability (YLDs) for 1160 Sequelae of 289 Diseases and Injuries 1990-2010: A Systematic Analysis for the Global Burden of Disease Study 2010. The Lancet, 380, 2163-2196.
[3] Mattsson, N.K., Karjalainen, P.K., Tolppanen, A.M., Heikkinen, A.M., Sintonen, H., Härkki, P., Nieminen, K. and Jalkanen, J. (2020) Pelvic Organ Prolapse Surgery and Quality of Life—A Nationwide Cohort Study. American Journal of Obstetrics and Gynecology, 222, 588.E1-588.E10.
https://doi.org/10.1016/j.ajog.2019.11.1285
[4] Dietrich, W., Elenskaia, K., Obermayr, E., Horvat, R., Mayerhofer, K., Umek, W., Zeillinger, R. and Hanzal, E. (2012) Relaxin and Gonadal Steroid Receptors in Uterosacral Ligaments of Women with and without Pelvic Organ Prolapse. International Urogynecology Journal, 23, 495-500.
https://doi.org/10.1007/s00192-011-1615-9
[5] Swift, S., Woodman, P., O’Boyle, A., Kahn, M., Valley, M., Bland, D., Wang, W. and Schaffer, J. (2005) Pelvic Organ Support Study (POSST): The Distribution, Clinical Definition, and Epidemiologic Condition of Pelvic Organ Support Defects. American Journal of Obstetrics and Gynecology, 192, 795-806.
https://doi.org/10.1016/j.ajog.2004.10.602
[6] Vergeldt, T.F.M., Weemhoff, M., IntHout, J. and Kluivers, K.B. (2015) Risk Factors for Pelvic Organ Prolapse and Its Recurrence: A Systematic Review. International Urogynecology Journal, 26, 1559-1573.
https://doi.org/10.1007/s00192-015-2695-8
[7] Niblock, K., Bailie, E., McCracken, G. and Johnston, K. (2017) Vaginal McCall Culdoplasty versus Laparoscopic Uterosacral Pliation to Prophylactically Address Vaginal Vault Prolapse. Gynecological Surgery, 14, Article No. 3.
https://doi.org/10.1186/s10397-017-1006-4
[8] Zhao, X., Ma, C., Li, R., Xue, J., Liu, L. and Liu, P. (2017) Hypoxia Induces Apoptosis through HIF-1α Signaling Pathway in Human Uterosacral Ligaments of Pelvic Organ Prolapse. BioMed Research International, 2017, Article ID: 8316094.
https://doi.org/10.1155/2017/8316094
[9] Sun, M.J., Cheng, Y.S., Liu, C.S. and Sun, R. (2019) Changes in the PGC-1α and mtDNA Copy Number May Play a Role in the Development of Pelvic Organ Prolapse in Pre-Menopausal Patients. Taiwanese Journal of Obstetrics and Gynecology, 58, 526-530.
https://doi.org/10.1016/j.tjog.2019.05.017
[10] Zhang, L., Zheng, P., Duan, A., Hao, Y., Lu, C. and Lu, D. (2019) [Corrigendum] Genome-Wide DNA Methylation Analysis of Uterosacral Ligaments in Women with Pelvic Organ Prolapse. Molecular Medicine Reports, 19, 2458.
https://doi.org/10.3892/mmr.2019.9852
[11] Tyagi, T., Alarab, M., Leong, Y., Lye, S. and Shynlova, O. (2019) Local Oestrogen Therapy Modulates Extracellular Matrix and Immune Response in the Vaginal Tissue of Post-Menopausal Women with Severe Pelvic Organ Prolapse. Journal of Cellular and Molecular Medicine, 23, 2907-2919.
https://doi.org/10.1111/jcmm.14199
[12] Alarab, M., Kufaishi, H., Lye, S., Drutz, H. and Shynlova, O. (2014) Expression of Extracellular Matrix-Remodeling Proteins Is Altered in Vaginal Tissue of Premenopausal Women with Severe Pelvic Organ Prolapse. Reproductive Sciences, 21, 704-715.
https://doi.org/10.1177/1933719113512529
[13] De Landsheere, L., Blacher, S., Munaut, C., Nusgens, B., Rubod, C., Noel, A., Foidart, J.M., Cosson, M. and Nisolle, M. (2014) Changes in Elastin Density in Different Locations of the Vaginal Wall in Women with Pelvic Organ Prolapse. International Urogynecology Journal, 25, 1673-1681.
https://doi.org/10.1007/s00192-014-2431-9
[14] Strinic, T., Vulic, M., Tomic, S., Capkun, V., Stipic, I. and Alujevic, I. (2010) Increased Expression of Matrix Metalloproteinase-1 in Uterosacral Ligament Tissue from Women with Pelvic Organ Prolapse. Acta Obstetricia et Gynecologica Scandinavica, 89, 832-834.
https://doi.org/10.3109/00016341003592545
[15] Min, J., Li, B., Liu, C., Guo, W., Hong, S., Tang, J. and Hong, L. (2017) Extracellular Matrix Metabolism Disorder Induced by Mechanical Strain on Human Parametrial Ligament Fibroblasts. Molecular Medicine Reports, 15, 3278-3284.
https://doi.org/10.3892/mmr.2017.6372
[16] Qi, X., Hong, L., Guo, F., Fu, Q., Chen, L. and Li, B. (2011) Expression of Transforming Growth Factor-β1 and Connective Tissue Growth Factor in Women with Pelvic Organ Prolapse. Saudi Medical Journal, 32, 474-478.
[17] Li, B.S., Hong, L., Min, J., Wu, D., Hu, M. and Guo, W.J. (2013) The Expression of Glutathione Peroxidase-1 and the Anabolism of Collagen Regulation Pathway Transforming Growth Factor-β1-Connective Tissue Growth Factor in Women with Uterine Prolapse and the Clinic Significance. Clinical and Experimental Obstetrics & Gynecology, 40, 586-590.
[18] Wen, Y., Polan, M.L. and Chen, B. (2006) Do Extracellular Matrix Protein Expressions Change with Cyclic Reproductive Hormones in Pelvic Connective Tissue from Women with Stress Urinary Incontinence? Human Reproduction, 21, 1266-1273.
https://doi.org/10.1093/humrep/dei485
[19] Meijerink, A.M., van Rijssel, R.H. and van der Linden, P.J.Q. (2013) Tissue Composition of the Vaginal Wall in Women with Pelvic Organ Prolapse. Gynecologic and Obstetric Investigation, 75, 21-27.
https://doi.org/10.1159/000341709
[20] Zhao, Y., Xia, Z., Lin, T. and Qin, M. (2021) Transforming Growth Factor Beta 1 and p44/42 Expression in Cardinal Ligament Tissues of Patients with Pelvic Organ Prolapse. Medical Science Monitor, 27, e930433.
https://doi.org/10.12659/MSM.930433
[21] Bump, R.C., Mattiasson, A., Bø, K., Brubaker, L.P., DeLancey, J.O., Klarskov, P., Shull, B.L. and Smith, A.R. (1996) The Standardization of Terminology of Female Pelvic Organ Prolapse and Pelvic Floor Dysfunction. American Journal of Obstetrics and Gynecology, 175, 10-17.
https://doi.org/10.1016/S0002-9378(96)70243-0
[22] Carlin, G.L., Bodner, K., Kimberger, O., Haslinger, P., Schneeberger, C., Horvat, R., Kölbl, H., Umek, W. and Bodner-Adler, B. (2020) The Role of Transforming Growth Factor-ß (TGF-ß1) in Postmenopausal Women with Pelvic Organ Prolapse: An Immunohistochemical Study. European Journal of Obstetrics & Gynecology and Reproductive Biology: X, 7, Article ID: 100111.
https://doi.org/10.1016/j.eurox.2020.100111
[23] Wilson, M.S. and Wynn, T.A. (2009) Pulmonary Fibrosis: Pathogenesis, Etiology and Regulation. Mucosal Immunology, 2, 103-121.
https://doi.org/10.1038/mi.2008.85
[24] Jackson, S.R., Eckford, S.D., Abrams, P., Avery, N.C., Tarlton, J.F. and Bailey, A.J. (1996) Changes in Metabolism of Collagen in Genitourinary Prolapse. The Lancet, 347, 1658-1661.
https://doi.org/10.1016/S0140-6736(96)91489-0
[25] Pascual, G., Corrales, C., Gómez-Gil, V., Buján, J. and Bellón, J.M. (2007) TGF-β1 Overexpression in the Transversalis Fascia of Patients with Direct Inguinal Hernia. European Journal of Clinical Investigation, 37, 516-521.
https://doi.org/10.1111/j.1365-2362.2007.01816.x
[26] Pan, S., Zhou, Y., Yan, L., Xuan, F., Tong, J., Li, Y., Huang, J., Feng, W., Chen, S., Cui, Y., Yang, F., Tan, S., Wang, Z., Tian, B., Hong, L.E., Tan, Y.L. and Tian, L. (2022) TGF-β1 Is Associated with Deficits in Cognition and Cerebral Cortical Thickness in First-Episode Schizophrenia. Journal of Psychiatry & Neuroscience, 47, E86-E98.
https://doi.org/10.1503/jpn.210121
[27] Loh, J.K., Lieu, A.S., Su, Y.F., Cheng, C.Y., Tsai, T.H., Lin, C.L., Lee, K.S., Hwang, S.L., Kwan, A.L., Wang, C.J., Hong, Y.R., Chio, C.C. and Howng, S.L. (2013) Plasma Levels of Transforming Growth Factor-β1 before and after Removal of Low- and High-Grade Astrocytomas. Cytokine, 61, 413-418.
https://doi.org/10.1016/j.cyto.2012.11.011
[28] Kuchtey, J., Kunkel, J., Burgess, L.G., Parks, M.B., Brantley, M.A.J. and Kuchtey, R.W. (2014) Elevated Transforming Growth Factor β1 in Plasma of Primary Open-Angle Glaucoma Patients. Investigative Ophthalmology & Visual Science, 55, 5291-5297.
https://doi.org/10.1167/iovs.14-14578
[29] Nikolić-Vukosavljević, D., Todorović-Raković, N., Demajo, M., Ivanović, V., Nesković, B., Markićević, M. and Nesković-Konstantinović, Z. (2004) Plasma TGF-β1-Related Survival of Postmenopausal Metastatic Breast Cancer Patients. Clinical & Experimental Metastasis, 21, 581-585.
https://doi.org/10.1007/s10585-004-4978-1
[30] Ivanović, V., Demajo, M., Krtolica, K., Krajnović, M., Konstantinović, M., Baltić, V., Prtenjak, G., Stojiljković, B., Breberina, M., Nesković-Konstantinović, Z., Nikolić-Vukosavljević, D. and Dimitrijević, B. (2006) Elevated Plasma TGF-β1 Levels Correlate with Decreased Survival of Metastatic Breast Cancer Patients. Clinica Chimica Acta, 371, 191-193.
https://doi.org/10.1016/j.cca.2006.02.027
[31] Rübe, C.E., Palm, J., Erren, M., Fleckenstein, J., König, J., Remberger, K. and Rübe, C. (2008) Cytokine Plasma Levels: Reliable Predictors for Radiation Pneumonitis? PLOS ONE, 3, e2898.
https://doi.org/10.1371/journal.pone.0002898
[32] Wang, Q., Ou, T., Li, J., Cui, X. and Liang, J. (2020) Research on the Association of Plasma TGF-β1 Level and Blood Lymphocyte/Monocyte Ratio with Pathological Grade, Clinical Stage and Prognosis of Prostate Cancer. Journal of Balkan Union of Oncology, 25, 2418-2423.
[33] Juarez, I., Gutierrez, A., Vaquero-Yuste, C., Molanes-López, E.M., López, A., Lasa, I., Gómez, R. and Martin-Villa, J.M. (2021) TGFB1 Polymorphisms and TGF-β1 Plasma Levels Identify Gastric Adenocarcinoma Patients with Lower Survival Rate and Disseminated Disease. Journal of Cellular and Molecular Medicine, 25, 774-783.
https://doi.org/10.1111/jcmm.16131
[34] Manjari, K.S., Jyothy, A., Vidyasagar, A., Prabhakar, B., Nallari, P. and Venkateshwari, A. (2013) Matrix Metalloproteinase-9, Transforming Growth Factor-β1, and Tumor Necrosis Factor-α Plasma Levels in Chronic Pancreatitis. Indian Journal of Gastroenterology, 32, 103-107.
https://doi.org/10.1007/s12664-012-0299-5
[35] Li, J., Yang, Y., Ng, C.Y., Zhang, Z., Liu, T. and Li, G. (2016) Association of Plasma Transforming Growth Factor-β1 Levels and the Risk of Atrial Fibrillation: A Meta-Analysis. PLOS ONE, 11, e0155275.
https://doi.org/10.1371/journal.pone.0155275
[36] Lijnen, P.J., Petrov, V.V. and Fagard, R.H. (2003) Association between Transforming Growth Factor-β and Hypertension. American Journal of Hypertension, 16, 604-611.
https://doi.org/10.1016/S0895-7061(03)00847-1
[37] Matsuki, K., Hathaway, C.K., Lawrence, M.G., Smithies, O. and Kakoki, M. (2014) The Role of Transforming Growth Factor β1 in the Regulation of Blood Pressure. Current Hypertension Reviews, 10, 223-238.
https://doi.org/10.2174/157340211004150319123313
[38] Kumar, P., Stiernborg, M., Fogdell-Hahn, A., Månsson, K., Furmark, T., Berglind, D., Melas, P.A., Forsell, Y. and Lavebratt, C. (2022) Physical Exercise Is Associated with a Reduction in Plasma Levels of Fractalkine, TGF-β1, Eotaxin-1 and IL-6 in Younger Adults with Mobility Disability. PLOS ONE, 17, e0263173.
https://doi.org/10.1371/journal.pone.0263173
[39] Chen, Y., Huang, M., Yan, Y. and He, D. (2021) Tranilast Inhibits Angiotensin II-Induced Myocardial Fibrosis Through S100A11/Transforming Growth Factor-β1 (TGF-β1)/Smad Axis. Bioengineered, 12, 8447-8456.
https://doi.org/10.1080/21655979.2021.1982322
[40] Nishijima, S., Sugaya, K., Kadekawa, K., Ashitomi, K., Ueda, T. and Yamamoto, H. (2013) High-Dose Tranilast Administration to Rats Creates Interstitial Cystitis-Like Symptoms with Increased Vascular Permeability. Life Sciences, 93, 897-903.
https://doi.org/10.1016/j.lfs.2013.10.010

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