Ovarian follicular growth and atresia: the relationship between cell proliferation and survival.
Ovarian follicular growth and atresia: the relationship between cell proliferation and survival.
复制标题
DOI：
10.2527/2004.8213_supple40x
复制
发表时间：
2004
影响因子：
3.3
通讯作者：
S. Quirk;R. Cowan;R. Harman;Che‐lin Hu;Dale A. Porter
中科院分区：
文献类型：
--
作者：
S. Quirk;R. Cowan;R. Harman;Che‐lin Hu;Dale A. Porter
生长因子和类固醇激素在卵巢卵泡发育的调节中起重要作用。在牛中，选择发育到排卵期的健康优势卵泡和注定要经历闭锁的次级卵泡之间最早可检测到的两个差异是IGF的更大可用性和优势卵泡中产生雌二醇的更大能力。我们已经证明，IGF-I和雌二醇刺激体外牛颗粒细胞的增殖，并通过增加对凋亡的抵抗力来促进颗粒细胞的存活。此外，IGF-I和雌二醇增加细胞凋亡抗性的能力与其促进细胞周期进展的能力有关。在第一间隙期和DNA合成期之间的过渡期使用特异性抑制剂阻断细胞周期，阻止了IGF-I和雌二醇对细胞凋亡的保护作用。进一步的实验表明IGF-I对细胞凋亡的保护作用是通过刺激磷脂酰肌醇3-激酶及其下游靶蛋白激酶B/Akt介导的。重组Akt腺病毒感染颗粒细胞后，Akt的组成性激活可防止细胞凋亡，这种作用也依赖于细胞周期进程。这些实验表明，雌二醇和IGF-I对细胞凋亡的保护作用取决于细胞周期的不受干扰的进展。一旦卵泡发育到排卵前阶段，LH峰诱导颗粒细胞终末分化并退出细胞周期。牛颗粒细胞退出细胞周期的12小时后，LH激增，成为抗凋亡，即使在生长因子的情况下。孕酮受体拮抗剂在体外治疗引起颗粒细胞重新进入细胞周期和对凋亡的敏感性，这表明LH峰诱导孕酮受体表达是细胞周期退出和抗凋亡所必需的。总之，颗粒细胞对凋亡的敏感性取决于细胞周期。生长卵泡中的卵泡颗粒细胞的存活依赖于生长因子，而对LH峰有终末分化反应的细胞对凋亡有抵抗力，并且相对独立于生长因子的存活。
Growth factors and steroids play an important role in the regulation of ovarian follicular development. In cattle, two of the earliest detectable differences between the healthy dominant follicle selected for development to the ovulatory stage and subordinate follicles destined to undergo atresia are the greater availability of IGF and the greater capacity to produce estradiol in the dominant follicle. We have shown that IGF-I and estradiol stimulate the proliferation of bovine granulosa cells in vitro and promote granulosa cell survival by increasing resistance to apoptosis. Furthermore, the ability of IGF-I and estradiol to increase resistance to apoptosis is tied to their ability to promote progression through the cell cycle. Blocking the cell cycle at the transition between the first gap phase and the DNA synthesis phase using a specific inhibitor prevented the protective effects of IGF-I and estradiol against apoptosis. Further experiments showed that the protective effect of IGF-I against apoptosis is mediated by the stimulation of phosphatidylinositol 3-kinase and its downstream target, protein kinase B/Akt. Constitutive activation of Akt by the infection of granulosa cells with a recombinant Akt adenovirus protected against apoptosis, and this effect also depended on cell cycle progression. These experiments show that the protective effect of estradiol and IGF-I against apoptosis depends on unperturbed progression through the cell cycle. Once follicles have developed to the preovulatory stage, the LH surge induces terminal differentiation of granulosa cells and withdrawal from the cell cycle. Bovine granulosa cells withdraw from the cell cycle by 12 h after the LH surge and become resistant to apoptosis, even in the absence of growth factors. Treatment with a progesterone receptor antagonist in vitro caused reentry of granulosa cells into the cell cycle and susceptibility to apoptosis, suggesting that induction of progesterone receptor expression by the LH surge is required for cell cycle withdrawal and resistance to apoptosis. In summary, the susceptibility of granulosa cells to apoptosis depends on the cell cycle. Proliferating granulosa cells in growing follicles depend on growth factors for survival, whereas cells that have terminally differentiated in response to the LH surge are resistant to apoptosis and relatively independent of growth factors for survival.