Department of Reproductive Medicine and Child Development, Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), University of Pisa, Pisa, Italy.
Mol Hum Reprod. 2010 Oct;16(10):761-9. doi: 10.1093/molehr/gaq049. Epub 2010 Jun 14.
The aim of this study is the identification of direct endothelial regulation by the androgens testosterone (T) and dihydrotestosterone (DHT). We tested the effects of T and DHT on nitric oxide (NO) synthesis and on tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) expression in human endothelial cells and in ovariectomized (OVX) rats. The results showed that at physiological concentrations T and DHT increase endothelial synthesis of NO. This depends on a rapid recruitment of the extracellular-related kinase (ERK) 1/2 and of the phosphatidylinositol 3-OH kinase (PI3K)/Akt cascades, resulting in endothelial nitric oxide synthase (eNOS) Ser(1177)-phosphorylation. In addition, a later increase of eNOS expression is found. With supra-physiological amounts of T or DHT the induction of NO synthesis is lost. A concentration-related increase of t-PA expression starting from physiological concentrations of T or DHT is found, whereas PAI-1 is augmented only with higher doses. Although DHT exerts these actions through androgen receptors (AR), T acts in part through aromatase-dependent conversion to 17β-estradiol. Ovariectomy is associated with significant changes in eNOS, t-PA and PAI-1 expression in the aorta of Wistar rats and T and DHT result in modifications on eNOS, PAI-1 and t-PA that are in line with the in vitro experiments. In conclusion, T and DHT act on endothelial cells through AR or via conversion to estradiol. Physiological, but not higher amounts are associated with enhanced NO synthesis and an increased t-PA/PAI-1 ratio. These findings are useful to understand the impact of androgens in ageing individuals.
本研究旨在确定雄激素睾酮（T）和二氢睾酮（DHT）对内皮细胞的直接调节作用。我们检测了 T 和 DHT 对人内皮细胞和去卵巢（OVX）大鼠中一氧化氮（NO）合成以及组织型纤溶酶原激活物（t-PA）和纤溶酶原激活物抑制剂-1（PAI-1）表达的影响。结果表明，在生理浓度下，T 和 DHT 增加内皮细胞中 NO 的合成。这依赖于细胞外相关激酶（ERK）1/2 和磷酸肌醇 3-OH 激酶（PI3K）/Akt 级联的快速募集，导致内皮型一氧化氮合酶（eNOS）Ser(1177)-磷酸化。此外，还发现 eNOS 表达的后期增加。用超生理量的 T 或 DHT，诱导 NO 合成的作用丧失。发现从 T 或 DHT 的生理浓度开始，t-PA 表达呈浓度依赖性增加，而 PAI-1 仅在较高剂量时增加。虽然 DHT 通过雄激素受体（AR）发挥这些作用，但 T 部分通过芳香酶依赖性转化为 17β-雌二醇起作用。去卵巢与 Wistar 大鼠主动脉中 eNOS、t-PA 和 PAI-1 表达的显著变化相关，T 和 DHT 导致 eNOS、PAI-1 和 t-PA 的改变与体外实验一致。总之，T 和 DHT 通过 AR 或转化为雌二醇作用于内皮细胞。生理量而不是更高量与增强的 NO 合成和增加的 t-PA/PAI-1 比值相关。这些发现有助于理解雄激素在衰老个体中的作用。
