Pascuali Natalia, Scotti Leopoldina, Abramovich Dalhia, Irusta Griselda, Di Pietro Mariana, Bas Diana, Tesone Marta, Parborell Fernanda
Instituto de Biología y Medicina Experimental (IByME), CONICET, Buenos Aires, Argentina.
Instituto de Biología y Medicina Experimental (IByME), CONICET, Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas, Universidad de Buenos Aires, Buenos Aires, Argentina.
Mol Cell Endocrinol. 2015 Sep 5;412:148-58. doi: 10.1016/j.mce.2015.04.021. Epub 2015 Apr 29.
The platelet-derived growth factor (PDGF) system is crucial for blood vessel stability. In the present study, we evaluated whether PDGFs play a critical intraovarian survival role in gonadotropin-dependent folliculogenesis. We examined the effect of intrabursal administration of a selective platelet-derived growth factor receptor (PDGFR) inhibitor (AG1295) on follicular development, proliferation, apoptosis and blood vessel formation and stability in ovaries from rats treated with equine chorionic gonadotropin (eCG). The percentages of preantral follicles (PAFs) and early antral follicles (EAFs) were lower in AG1295-treated ovaries than in control ovaries (p < 0.01-0.05). The percentage of atretic follicles (AtrFs) increased in AG1295-treated ovaries compared to control (p < 0.05). The ovarian weight and estradiol concentrations were lower in AG1295-treated ovaries than in the control group (p < 0.01 and p < 0.05, respectively), whereas progesterone concentrations did not change. AG1295 decreased the proliferation index in EAFs (p < 0.05) and increased the percentage of nuclei positive for cleaved caspase-3 and apoptotic DNA fragmentation (p < 0.01-0.05). AG1295 increased the expression of Bax (p < 0.05) without changes in the expression of Bcl-2 protein. AG1295-treated ovaries increased the cleavage of caspase-8 (p < 0.05) and decreased AKT and BAD phosphorylation compared with control ovaries (p < 0.05). AG1295 caused a decrease not only in the endothelial cell area but also in the area of pericytes and vascular smooth muscle cells (VSMCs) in the ovary (p < 0.05). Our findings suggest that the local inhibition of PDGFs causes an increase in ovarian apoptosis through an imbalance in the ratio of antiapoptotic to proapoptotic proteins, thus leading a larger number of follicles to atresia. PDGFs could exert their mechanism of action through an autocrine/paracrine effect on granulosa and theca cells mediated by PDGFRs. In conclusion, these data clearly indicate that the PDGF system is necessary for follicular development induced by gonadotropins.
血小板衍生生长因子（PDGF）系统对血管稳定性至关重要。在本研究中，我们评估了PDGFs在促性腺激素依赖性卵泡发生过程中是否在卵巢内发挥关键的存活作用。我们研究了向囊内注射选择性血小板衍生生长因子受体（PDGFR）抑制剂（AG1295）对用马绒毛膜促性腺激素（eCG）处理的大鼠卵巢中卵泡发育、增殖、凋亡以及血管形成和稳定性的影响。与对照卵巢相比，AG1295处理的卵巢中初级卵泡（PAF）和早期窦状卵泡（EAF）的百分比更低（p < 0.01 - 0.05）。与对照相比，AG1295处理的卵巢中闭锁卵泡（AtrF）的百分比增加（p < 0.05）。AG1295处理的卵巢的重量和雌二醇浓度低于对照组（分别为p < 0.01和p < 0.05），而孕酮浓度没有变化。AG1295降低了EAF中的增殖指数（p < 0.05），并增加了裂解的半胱天冬酶 - 3阳性细胞核和凋亡DNA片段化的百分比（p < 0.01 - 0.05）。AG1295增加了Bax的表达（p < 0.05），而Bcl - 2蛋白的表达没有变化。与对照卵巢相比，AG1295处理的卵巢增加了半胱天冬酶 - 8的裂解（p < 0.05），并降低了AKT和BAD的磷酸化水平（p < 0.05）。AG1295不仅导致卵巢中内皮细胞面积减少，还导致周细胞和平滑肌细胞（VSMC）面积减少（p < 0.05）。我们的研究结果表明，局部抑制PDGFs会通过抗凋亡蛋白与促凋亡蛋白比例失衡导致卵巢细胞凋亡增加，从而使更多卵泡闭锁。PDGFs可能通过PDGFR介导的对颗粒细胞和卵泡膜细胞的自分泌/旁分泌作用发挥其作用机制。总之，这些数据清楚地表明PDGF系统对促性腺激素诱导的卵泡发育是必需的。
