Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo
Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo
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DOI：
10.1093/molehr/gaq049
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发表时间：
2010-10-01
影响因子：
4
通讯作者：
Simoncini, T.
中科院分区：
文献类型：
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作者：
Goglia, L.;Tosi, V.;Simoncini, T.
本研究的目的是确定雄激素睾酮(T)和双氢睾酮（DHT）对内皮细胞的直接调节。我们检测了T和DHT对人内皮细胞和去卵巢大鼠一氧化氮（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可增加内皮细胞NO的合成。这取决于细胞外相关激酶（ERK） 1/2和磷脂酰肌醇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表达量随后增加。当T或DHT超过生理量时，一氧化氮合成的诱导作用就丧失了。从T或DHT的生理浓度开始，发现T - pa表达的浓度相关增加，而PAI-1仅在较高剂量时才增加。虽然DHT通过雄激素受体（AR）发挥这些作用，但T的部分作用是通过芳香化酶依赖性转化为17 β -雌二醇。卵巢切除术与Wistar大鼠主动脉eNOS、T - pa和T - pa表达显著变化相关，T和DHT对eNOS、PAI-1和T - pa表达的影响与体外实验一致。综上所述，T和DHT通过AR或转化为雌二醇作用于内皮细胞。生理性的，但不是更高的量与增强的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对衰老个体的影响。
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 17 beta-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.