Endothelial Cell Proliferation in Male Reproductive Organs of Adult Rat Is High and Regulated by Testicular Factors1

Lissbrant, Ingela Franck; Lissbrant, Erik; Persson, Anette; Damber, Jan‐Erik; Bergh, Anders

doi:10.1095/biolreprod.102.008284

Cited by 38 publications

(20 citation statements)

References 32 publications

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“…To further characterize the effect of DEX on specific compartments of the seminiferous tubules and on spermatogenesis, we employed three immunohistochemical biomarkers: Ki-67, prominently expressed in the nuclei of mitotic spermatogonia and meiotic primary spermatocytes; serves as proliferating index in testis (Lissbrant et al 2003). PCNA, involved in DNA replication and repair, also prominently expressed in the nuclei of spermatogonia and primary spermatocytes (Chapman & Wolgemuth 1994, Kamel et al 1997, Steger et al 1998, Bar-Shira Maymon et al 2003.…”

Section: Discussionmentioning

confidence: 99%

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Levi¹,

Tzabari²,

Savion³

et al. 2015

Reproduction

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Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5 mg/kg DXR, 100 mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity. Reproduction (2015) 150 357-366

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Section: Discussionmentioning

confidence: 99%

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Levi¹,

Tzabari²,

Savion³

et al. 2015

Reproduction

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“…However, the involvement of hormones and/or gonadal factors other than testosterone cannot be ruled out. Thus, vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-b, or hyalurodinase with gonadal origin (Lissbrant et al 2003) could all play an important role in vascular function (Rahmanian & Heldin 2002). Therefore, we studied the possible modification of EFSinduced TXA 2 release by endogenous male sex hormones.…”

Section: Discussionmentioning

confidence: 99%

Orchidectomy increases the formation of non-endothelial thromboxane A2 and modulates its role in the electrical field stimulation-induced response in rat mesenteric artery

Campo¹,

Sagredo²,

Aras-López³

et al. 2008

Journal of Endocrinology

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The aim of this study was to analyze whether endogenous male sex hormones influence the release of thromboxane A 2 (TXA 2 ) and its role in the electrical field stimulation (EFS)-induced response, as well as the mechanism involved. For this purpose, endothelium-denuded mesenteric arteries from control and orchidectomized male Sprague-Dawley rats were used to measure TXA 2 release; EFS-induced response, nitric oxide (NO), norepinephrine (NA), and prostaglandin (PG) I 2 release were also measured in the presence of the TXA 2 synthesis inhibitor furegrelate. Orchidectomy increased basal and EFS-induced TXA 2 release. Furegrelate decreased the EFS-induced contraction in arteries from control rats, but did not modify it in arteries from orchidectomized rats. The EFS-induced neuronal NO release and vasodilator response were increased by furegrelate in arteries from control rats, but were not modified in arteries from orchidectomized rats. Furegrelate did not modify the EFS-induced NA release or vasoconstrictor response in arteries from either control or orchidectomized rats. The EFS-induced PGI 2 release was not modified by furegrelate in arteries from control rats, but was increased in arteries from orchidectomized rats. The results of the present study show that endogenous male sex hormone deprivation i) increases non-endothelial TXA 2 release and ii) regulates the effect of endogenous TXA 2 on the EFS-induced response through different mechanisms that, at the least, involve the NO and PGI 2 systems. In arteries from control rats, inhibition of TXA 2 formation decreases the EFS-induced response by increasing neuronal NO release. In arteries from orchidectomized rats, the EFS-induced response is unaltered after the inhibition of TXA 2 formation, by increasing PGI 2 release.

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“…33 Testosterone stimulates endothelial proliferation and vascular regrowth (angiogenesis) after castration, however these may be secondary, due to hypoxia. 34,35 In culture, androgens stimulate angiogenic factors via HIF-1. 36 The loss of angiogenesis inhibitors in PrCa has been demonstrated, 33,37 however direct androgen suppression was only shown for pigment epithelial-derived factor (PEDF).…”

mentioning

confidence: 99%

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

Nelius

Filleur

Yemelyanov

et al. 2007

Intl Journal of Cancer

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The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NFjB, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NFjB suppression, since it was restricted to the cells lacking nuclear (active) NFjB. Thus we for the first time identified combined decrease of NFjB and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. ' 2007 Wiley-Liss, Inc.

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Endothelial Cell Proliferation in Male Reproductive Organs of Adult Rat Is High and Regulated by Testicular Factors1

Cited by 38 publications

References 32 publications

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

Orchidectomy increases the formation of non-endothelial thromboxane A2 and modulates its role in the electrical field stimulation-induced response in rat mesenteric artery

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

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