Adesanya O O, Zhou J, Bondy C A
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Clin Endocrinol Metab. 1996 Jul;81(7):2495-501. doi: 10.1210/jcem.81.7.8675566.
Insulin-like growth factors (IGF)-I and -II are abundant in the primate myometrium and are implicated in the sex steroid-induced growth of this tissue. To evaluate the potential for modulation of IGF action in the primate myometrium by locally produced IGF binding proteins (IGFBPs), we examined the cellular localization and sex steroid regulation of IGFBPs 1-5 in the nonhuman primate uterus. Ovariectomized rhesus monkeys were treated with placebo, estradiol (E2), or E2 and progesterone (P4) (E2 and P4) for 2 weeks, after which their uteri were removed and cut into thin serial sections for analysis by in situ hybridization. IGFBP-1 messenger RNA (mRNA) was not detected in control or E2-treated uteri but was found in a few unidentified cells in the E2 and P4-treated group. IGFBP-2, -3, -4, and -5 mRNAs were all expressed by myometrial smooth muscle cells but each displayed distinctive patterns of regulation by sex steroids. IGFBP-2 was barely detectable in control myometrium, was significantly increased by E2 and even more significantly by E2 and P4. IGFBP-4 and 5 mRNAs were readily detectable in control myometrium and significantly increased by E2 treatment. The addition of P4 to E2 treatment did not produce a significantly greater augmentation in IGFBP-4 or 5mRNA level compared with E2 alone. IGFBP-3 mRNA was abundant in the control myometrium, but in contrast to other IGFBPs was significantly reduced by approximately 75% in smooth muscle cells by E2 and by E2 and P4 treatment. Interestingly, however, IGFBP-3 mRNA was increased in the uterine vascular endothelium by E2 and by E2 and P4 treatment. In summary, this study has shown that four of the six known IGFBPs are highly expressed in the primate myometrium, and that their expression is differentially regulated by sex steroids. The cellular and sex steroid-regulated pattern of IGFBP-2 gene expression is very similar to that of IGF-I, as previously determined in these same myometrial samples. Both IGF-I and IGFBP-2 are dependent on E2 for significant myometrial expression, and both are further augmented by the addition of P4 to E2 treatment. Uterine smooth muscle IGFBP-3 mRNA levels are negatively regulated, whereas IGFBP-4 and -5 mRNA levels are positively regulated by E2: none of these myometrial IGFBPs appears sensitive to the effects of P4. The present observations, together with our previous data from the same animals, demonstrate that the primate myometrial smooth muscle cell expresses mRNAs for IGF-I and -II, IGF-I and -II receptors, as well as expresses mRNAs for IGFBP-2, -3, -4, and -5. These data provide evidence for complex local interactions between IGF system components regulated by estrogen and progesterone.
胰岛素样生长因子（IGF）-I和-II在灵长类动物子宫肌层中含量丰富，且与该组织的性类固醇诱导生长有关。为了评估局部产生的IGF结合蛋白（IGFBP）对灵长类动物子宫肌层中IGF作用的调节潜力，我们研究了IGFBP 1-5在非人类灵长类动物子宫中的细胞定位和性类固醇调节。将去卵巢的恒河猴用安慰剂、雌二醇（E2）或E2加孕酮（P4）（E2+P4）处理2周，之后切除子宫并切成薄的连续切片，通过原位杂交进行分析。在对照或E2处理的子宫中未检测到IGFBP-1信使核糖核酸（mRNA），但在E2+P4处理组的一些未识别细胞中发现了它。IGFBP-2、-3、-4和-5的mRNA均由子宫肌层平滑肌细胞表达，但每种都表现出独特的性类固醇调节模式。对照子宫肌层中几乎检测不到IGFBP-2，E2使其显著增加，E2+P4使其增加更显著。对照子宫肌层中很容易检测到IGFBP-4和5的mRNA，E2处理使其显著增加。与单独使用E2相比，E2处理中添加P4并未使IGFBP-4或5的mRNA水平有显著更大的增加。IGFBP-3的mRNA在对照子宫肌层中丰富，但与其他IGFBP不同，E2以及E2+P4处理使其在平滑肌细胞中显著降低约75%。然而，有趣的是，E2以及E2+P4处理使子宫血管内皮中的IGFBP-3 mRNA增加。总之，本研究表明，六种已知的IGFBP中的四种在灵长类动物子宫肌层中高度表达，且它们的表达受性类固醇的差异调节。IGFBP-2基因表达的细胞和性类固醇调节模式与IGF-I非常相似，如先前在这些相同的子宫肌层样本中所确定的。IGF-I和IGFBP-2在子宫肌层中的显著表达均依赖于E2，且E2处理中添加P4会使其进一步增加。子宫平滑肌IGFBP-3的mRNA水平受到负调节，而IGFBP-4和-5的mRNA水平受到E2的正调节：这些子宫肌层中的IGFBP似乎均对P4的作用不敏感。目前的观察结果，连同我们之前来自相同动物的数据，表明灵长类动物子宫肌层平滑肌细胞表达IGF-I和-II、IGF-I和-II受体的mRNA，以及IGFBP-2、-3、-4和-5的mRNA。这些数据为雌激素和孕酮调节的IGF系统成分之间复杂的局部相互作用提供了证据。
