Pleiotrophic functions of erythropoietin and regulation of its biosynthesis.

促红细胞生成素（EPO）是一种由成人肾脏产生的糖蛋白，作用于红系前体细胞，刺激其增殖和分化。促红细胞生成被认为是EPO的唯一功能，但我们发现EPO在中枢神经系统（CNS）和女性生殖器官中的新功能如下。(1)EPO受体表达于海马和大脑皮层。(2)EPO由中枢神经系统中的星形胶质细胞产生，其合成不仅受到缺氧的刺激，而且受到胰岛素和胰岛素样生长因子的刺激。生长因子的刺激是由于mRNA的增加。(3)EPO抑制谷氨酸诱导的培养神经元细胞死亡。由于这种毒性是缺血诱导的神经元死亡的主要原因，因此EPO似乎作为神经营养因子作用于神经元。脑内注射EPO可有效抑制缺血引起的海马神经元死亡和缺血引起的记忆学习能力下降。(4)血管生成是既存血管的延伸，除雌性生殖器官外，在成体中相对不活跃。子宫内膜在动物的发情周期和灵长类的月经周期中反复进行重构，并伴随着血管的生成。我们已经发现证据表明EPO参与子宫血管生成。(5)子宫内膜重塑受女性性激素，特别是卵巢产生的雌二醇的控制。雌激素能快速诱导卵巢切除小鼠EPO mRNA的表达。此外，在体外培养的子宫组织从卵巢切除小鼠产生EPO到培养基中雌二醇依赖的方式。(6)免疫组织化学染色显示EPO受体表达于子宫毛细血管内皮细胞。这些结果表明EPO在子宫血管生成中起重要作用。

Erythropoietin (EPO), a glycoprotein produced by kidney in the adults, acts on erythroid precursor cells, stimulating their proliferation and differentiation. Stimulation of erythropoiesis was believed to be a sole function of EPO but we have found novel functions of EPO in the central nervous system (CNS) and female reproductive organ as followings.(1) EPO receptor is expressed in hippocampus and cerebral cortex.(2) EPO is produced by astrocytes in CNS and its synthesis is stimulated not only by hypoxia but also by insulin and insulin-like growth factors. The stimulation by the growth factors is due to an increased mRNA.(3) EPO represses Glu-induced cell death of cultured neurons. Since this toxicity is the major cause of ischemia-induced neuronal death, it appears that EPO acts on neurons as a neurotrophic factor. Injection of EPO into gerbil brain suppressed with high efficiency ischemia-induced neuronal death in hippocampus and also ischemia-induced reduction in memory-learning ability.(4) Angiogenesis is the extension of preexsisting blood vessels and is relatively inactive in the adults except for female reproductive organ. Uterine endometrium repeats its remodeling in estrous cycle of animals and menstruation cycle of primates, which accompanies angiogenesis. We have found evidence showing that EPO is involved in uterine angiogenesis.(5) The endometrial remodeling is under control of female sexual hormone, particularly estradiol that is produced in ovary. When estradiol was given to ovariectomized mouse, rapid induction of EPO mRNA expression occurred. Furthermore, in vitro cultured uterine tissue from ovariectomized mouse produced EPO into culture media in an estradiol-dependent manner.(6) Immunohistochemical staining showed that EPO receptor is expressed in endothelial cells of uterine capillary. These results indicate that EPO plays an important role in uterine angiogenesis.