Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Dositeja Obradovica Square 2, Novi Sad 21000, Serbia.
Mol Hum Reprod. 2014 Jan;20(1):77-88. doi: 10.1093/molehr/gat052. Epub 2013 Jul 26.
The molecular mechanism of stress-associated reproductive dysfunction is complex and largely unknown. This study was designed to systematically analyze molecular effects of systemic in vivo blockade of α1-adrenergic receptors (α1-ADRs) on stress-induced disturbance of cAMP/cGMP signaling in testosterone-producing Leydig cells using the following parameters (i) level of circulating stress hormones, LH and testosterone; (ii) level of main molecular markers of Leydig cell functionality (testosterone, Insl3, cAMP); (iii) expression of cAMP signaling (cAMP 'producers'/'effectors'/'removers') and (iv) expression of NO-cGMP signaling (NO-cGMP 'producers'/'effectors'/'removers'). The results showed that oral administration of α1-ADR blocker before stress increased cGMP and diminished stress-reduced cAMP production in Leydig cells. In the same cells, stress-induced effects on cAMP/cGMP signaling pathways elements were changed. Sustained in vivo α1-ADR blockade completely abolished stress-increased transcription of most abundantly expressed phosphodiesterase that remove cAMP (Pde4b) and potentiated stress-increased expression of PRKA, the main stimulator of Leydig cell steroidogenesis. In the same Leydig cells, stress-decreased NOS3 expression was abolished, while stress-increased GUCY1 (cGMP 'producer') and PRKG1 (cGMP 'effector') were potentiated. It is possible that all molecules mentioned could contribute, at least in part, in recovery of Leydig cell testosterone production. Presented data provide new role of α1-ADRs in stress-triggered disturbance of cAMP/cGMP signaling, and new molecular insights into the relationship between stress and mammalian reproduction. Regardless of whether the effects of α1-blocker + stress are direct or indirect, the results are important in terms of human reproductive health and the wide use of α1-ADR antagonists, alone or in combination, to treat post-traumatic stress disorders, hypertension, benign prostatic hyperplasia symptoms and potential drugs for prostate cancer prevention/treatment.
应激相关生殖功能障碍的分子机制复杂且大部分未知。本研究旨在采用以下参数系统分析全身体内阻断 α1-肾上腺素能受体（α1-ADRs）对产生睾酮的莱迪希细胞中 cAMP/cGMP 信号应激诱导紊乱的分子影响：（i）循环应激激素、LH 和睾酮水平；（ii）莱迪希细胞功能的主要分子标记物（睾酮、Ins13、cAMP）水平；（iii）cAMP 信号表达（cAMP“产生物”/“效应物”/“清除物”）；（iv）NO-cGMP 信号表达（NO-cGMP“产生物”/“效应物”/“清除物”）。结果表明，应激前给予 α1-ADR 阻滞剂口服可增加莱迪希细胞中环磷酸鸟苷（cGMP）并减少应激减少的 cAMP 产生。在相同的细胞中，应激对 cAMP/cGMP 信号通路元素的影响发生变化。持续的体内 α1-ADR 阻断完全消除了应激增加的大部分表达的磷酸二酯酶（Pde4b）的转录，该酶去除 cAMP，同时增强了应激增加的 PRKA 的表达，PRKA 是莱迪希细胞类固醇生成的主要刺激物。在相同的莱迪希细胞中，应激减少的 NOS3 表达被消除，而应激增加的 GUCY1（cGMP“产生物”）和 PRKG1（cGMP“效应物”）被增强。可能提到的所有分子都至少部分有助于莱迪希细胞睾酮的产生恢复。提供的新数据表明 α1-ADRs 在应激触发的 cAMP/cGMP 信号紊乱中发挥新作用，并为应激与哺乳动物生殖之间的关系提供新的分子见解。无论 α1-阻滞剂+应激的影响是直接的还是间接的，这些结果对于人类生殖健康以及广泛使用 α1-ADR 拮抗剂（单独或联合使用）治疗创伤后应激障碍、高血压、良性前列腺增生症状和预防/治疗前列腺癌的潜在药物都非常重要。
