Pleiotrophic functions of erythropoietin and regulation of its biosynthesis.

促红细胞生成素（EPO）是成人肾脏产生的一种糖蛋白，作用于红细胞前体细胞，刺激其增殖和分化。促红细胞生成被认为是促红细胞生成的唯一功能，但我们发现促红细胞生成在中枢神经系统（CNS）和女性生殖器官中有以下新功能。(1) EPO受体在海马和大脑皮层表达。(2) EPO由中枢神经系统内的星形胶质细胞产生，其合成不仅受缺氧刺激，还受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glu诱导的神经元细胞死亡。由于这种毒性是缺血性神经元死亡的主要原因，EPO似乎作为一种神经营养因子作用于神经元。沙鼠脑内注射EPO可有效抑制海马缺血神经元死亡及缺血记忆学习能力下降。(4)血管生成是原有血管的延伸，除女性生殖器官外，成人血管生成相对不活跃。在动物的发情周期和灵长类动物的月经周期中，子宫内膜重复重构，并伴随血管生成。我们已经发现EPO参与子宫血管生成的证据。(5)子宫内膜重塑受女性性激素控制，尤其是卵巢产生的雌二醇。雌二醇给予去卵巢小鼠，可快速诱导EPO mRNA表达。此外，体外培养的卵巢切除小鼠子宫组织以雌二醇依赖的方式向培养基中产生EPO。(6)免疫组化染色显示EPO受体在子宫毛细血管内皮细胞中表达。提示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.