Paspaliaris V, Petersen D N, Thiede M A
Department of Cardiovascular and Metabolic Disease, Pfizer Central Research, Groton, CT 06340, USA.
J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):259-65. doi: 10.1016/0960-0760(95)00057-7.
The gene encoding parathyroid hormone-related protein (PTHrP), an autocrine/paracrine inhibitor of vascular and nonvascular smooth muscle contractility, is regulated by hormonal steroids including estrogens (E2), 1,25-dihydroxy vitamin D (Vit D3) and glucocorticoids. While E2 increases PTHrP gene expression, Vit D3 and glucocorticoids inhibit transcriptional activity of this gene. In the uterus of ovariectomized rats, E2-treatment increases both PTHrP mRNA levels and smooth muscle sensitivity to the action of PTHrP(1-34). To examine the action(s) of Vit D3 and glucocorticoids on these parameters, OVX rats were treated with E2, Vit D3 or the synthetic glucocorticoid, dexamethasone (Dex), alone, or with E2 following a 1 h pretreatment with Vit D3 or Dex. PTHrP and PTH/PTHrP receptor mRNA were measured by blot hybridization analysis of RNA prepared from uteri collected 2, 4 and 24 h after treatment. Uterine horns were used to measure the effect of the steroids on the ability of PTHrP(1-34) to inhibit spontaneous myometrial contraction. When E2, Vit D3 and Dex were given alone, only E2 altered PTHrP mRNA levels in the uterus, however, a 1 h pretreatment with Dex but not Vit D3 markedly diminished this effect of E2. The temporal decline in uterine PTH/PTHrP receptor mRNA levels measured 2 and 4 h after E2 treatment inversely correlated to changes in sensitivity of the tissue to PTHrP(1-34) measured at 24 h after E2 administration. In comparison to E2 alone, treatment with Vit D3 and E2 augmented the uterine responsiveness to PTHrP(1-34) while pretreatment with Dex (1 mg/kg) and E2 decreased this response. These data indicate that in the uterus, Dex opposes the positive effect of E2 on PTHrP gene activity and differentially modulates the action of PTHrP on myometrial tone. Moreover, elevations in the circulating levels of cortisol at term may serve to decrease both the uterine expression of PTHrP and the local action of PTHrP on the myometrium prior to parturition, therefore promoting myometrial contraction associated with labor.
编码甲状旁腺激素相关蛋白（PTHrP）的基因是血管和非血管平滑肌收缩的自分泌/旁分泌抑制剂，它受包括雌激素（E2）、1,25 - 二羟基维生素D（维生素D3）和糖皮质激素在内的激素调节。E2可增加PTHrP基因表达，而维生素D3和糖皮质激素则抑制该基因的转录活性。在去卵巢大鼠的子宫中，E2处理可增加PTHrP mRNA水平以及平滑肌对PTHrP(1 - 34)作用的敏感性。为了研究维生素D3和糖皮质激素对这些参数的作用，给去卵巢大鼠单独使用E2、维生素D3或合成糖皮质激素地塞米松（Dex）进行处理，或者在使用维生素D3或Dex预处理1小时后再使用E2。通过对处理后2、4和24小时收集的子宫RNA进行印迹杂交分析来检测PTHrP和PTH/PTHrP受体mRNA。使用子宫角来测量这些类固醇对PTHrP(1 - 34)抑制子宫肌层自发收缩能力的影响。单独给予E2、维生素D3和Dex时，只有E2改变了子宫中PTHrP mRNA水平，然而，用Dex预处理1小时而非维生素D3能显著减弱E2的这种作用。在E2处理后2小时和4小时测量的子宫PTH/PTHrP受体mRNA水平的暂时下降与在E2给药后24小时测量的组织对PTHrP(1 - 34)敏感性变化呈负相关。与单独使用E2相比，维生素D3和E2联合处理增强了子宫对PTHrP(1 - 34)的反应性，而用Dex（1mg/kg）预处理后再使用E2则降低了这种反应。这些数据表明，在子宫中，Dex对抗E2对PTHrP基因活性的积极作用，并差异调节PTHrP对子宫肌层张力的作用。此外，足月时循环中皮质醇水平的升高可能在分娩前降低子宫中PTHrP的表达以及PTHrP对子宫肌层的局部作用，从而促进与分娩相关的子宫肌层收缩。
