Dihydrotestosterone induces arterial stiffening in female mice.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-01-23 DOI:10.1186/s13293-024-00586-3
Alec C Horton, Mary M Wilkinson, Isabella Kilanowski-Doroh, Zhejun Dong, Jiao Liu, Benard O Ogola, Bruna Visniauskas, Sarah H Lindsey
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Abstract

Background: Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido. Androgens also circulate at higher levels in women with polycystic ovarian syndrome, a condition that increases the risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via downregulation of GPER.

Methods: The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice at 15-16 weeks of age were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n = 8-9/group).

Results: In cultured vascular smooth muscle cells, GPER mRNA was decreased by DHT (P = 0.001) but was not impacted by dexamethasone or medroxyprogesterone. In contrast, ERα expression in cultured cells was significantly suppressed by all three hormones (P < 0.0001). In control mice or mice treated with a single or double dose of DHT, a dose-dependent increase in body weight was observed (control 22 ± 2 g, single dose 24 ± 2 g, double dose 26 ± 2 g; P = 0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9 ± 0.3 m/s, single dose 4.3 ± 0.8 m/s, double dose 4.8 ± 1.0 m/s). This increase in arterial stiffness occurred independent of changes in blood pressure (P = 0.59). Histological analysis of aortic sections using Masson's trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P = 0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20 ± 5, single dose 10.5 ± 5.6, double dose 10 ± 4 copies/ng; P = 0.001) and ERα (control 54 ± 2, single dose 24 ± 13, and double dose 23 ± 12 copies/ng; P = 0.003).

Conclusions: These findings indicate that androgen promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.

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二氢睾酮诱导雌性小鼠动脉硬化
背景:雄性激素是男性和女性体内重要的性激素,当内源性雄性激素水平较低时、性别转换或提高性欲时都需要补充雄性激素。患有多囊卵巢综合征的女性体内雄激素的循环水平也较高,这种情况会增加患高血压和动脉僵化等心血管疾病的风险。由于我们之前的研究表明 G 蛋白偶联雌激素受体(GPER)在动脉僵化中起着重要作用,因此我们假设包括雄激素在内的其他激素可能会通过下调 GPER 影响雌性小鼠的动脉僵化:方法:在培养的血管平滑肌细胞中,使用液滴数字 PCR(ddPCR)评估了非芳香化雄激素双氢睾酮(DHT)、糖皮质激素地塞米松和孕激素醋酸甲羟孕酮(均为 100 nM,持续 24 小时)对 GPER 和 ERα 表达的影响。为了评估DHT诱导的GPER下调在体内的影响,用含有DHT的硅胶胶囊对15-16周龄的雌性卵巢接触C57Bl/6小鼠进行了为期4周的治疗,其中一个剂量预期模拟人类雄性DHT水平,另一个剂量预期为人类浓度的两倍(n = 8-9/组):在培养的血管平滑肌细胞中,GPER mRNA 受 DHT 影响而降低(P = 0.001),但不受地塞米松或甲羟孕酮的影响。与此相反,培养细胞中的 ERα 表达受到这三种激素的显著抑制(P 结论:DHT、地塞米松和甲羟孕酮均能抑制 ERα 的表达):这些研究结果表明,雄激素会促进雌性小鼠动脉僵化和心血管损伤,并与雌激素受体表达减少有关。这些数据对于变性男性、因健身或性欲减退而使用睾酮的女性以及多囊卵巢综合征患者来说非常重要。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
Sex differences in the role of AKAP12 in behavioral function of middle-aged mice. Sex differences in the human brain related to visual motion perception. A call for inclusive research, policies, and leadership to close the global women's health gap. Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment. Sex dimorphism and tissue specificity of gene expression changes in aging mice.
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