Montt-Guevara Maria Magdalena, Giretti Maria Silvia, Russo Eleonora, Giannini Andrea, Mannella Paolo, Genazzani Andrea Riccardo, Genazzani Alessandro David, Simoncini Tommaso
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
Department of Obstetrics and Gynecology, University of Modena and Reggio Emilia , Modena , Italy.
Front Endocrinol (Lausanne). 2015 Jul 22;6:111. doi: 10.3389/fendo.2015.00111. eCollection 2015.
Estetrol (E4) is a natural human estrogen that is present at high concentrations during pregnancy. E4 has been reported to act as an endogenous estrogen receptor modulator, exerting estrogenic actions on the endometrium or the central nervous system but presenting antagonistic effects on the breast. Due to these characteristics, E4 is currently being developed for a number of clinical applications, including contraception and menopausal hormone therapy. Endothelial nitric oxide (NO) is a key player for vascular function and disease during pregnancy and throughout aging in women. Endothelial NO is an established target of estrogens that enhance its formation in human endothelial cells. We here addressed the effects of E4 on the activity and expression of the endothelial nitric oxide synthase (eNOS) in cultured human umbilical vein endothelial cells (HUVEC). E4 stimulated the activation of eNOS and NO secretion in HUVEC. E4 was significantly less effective compared to E2, and a peculiar concentration-dependent effect was found, with higher amounts of E4 being less effective than lower concentrations. When E2 was combined with E4, an interesting pattern was noted. E4 antagonized NO synthesis induced by pregnancy-like E2 concentrations. However, E4 did not impede the modest induction of NO synthesis associated with postmenopausal-like E2 levels. These results support the hypothesis that E4 may be a regulator of NO synthesis in endothelial cells and raise questions on its peculiar signaling in this context. Our results may be useful to interpret the role of E4 during human pregnancy and possibly to help develop this interesting steroid for clinical use.
雌三醇（E4）是一种天然的人体雌激素，在孕期以高浓度存在。据报道，E4可作为一种内源性雌激素受体调节剂，对子宫内膜或中枢神经系统发挥雌激素作用，但对乳腺呈现拮抗作用。由于这些特性，E4目前正被开发用于多种临床应用，包括避孕和更年期激素治疗。内皮型一氧化氮（NO）是孕期及女性整个衰老过程中血管功能和疾病的关键因素。内皮型NO是雌激素的既定靶点，雌激素可增强其在人内皮细胞中的生成。我们在此研究了E4对培养的人脐静脉内皮细胞（HUVEC）中内皮型一氧化氮合酶（eNOS）活性和表达的影响。E4刺激了HUVEC中eNOS的激活和NO分泌。与E2相比，E4的效果明显较差，并且发现了一种特殊的浓度依赖性效应，即较高剂量的E4比较低浓度的效果更差。当E2与E4联合使用时，观察到一种有趣的模式。E4拮抗类似孕期E2浓度诱导的NO合成。然而，E4并不妨碍与类似绝经后E2水平相关的适度NO合成诱导。这些结果支持了E4可能是内皮细胞中NO合成调节剂的假设，并引发了关于其在这种情况下特殊信号传导的问题。我们的结果可能有助于解释E4在人类孕期的作用，并可能有助于开发这种有趣的类固醇用于临床应用。
