孕酮受体拮抗剂可拮抗创伤性脑损伤大鼠体内内皮祖细胞的孕酮介导血管生成活性及血管生成。
Progesterone-mediated angiogenic activity of endothelial progenitor cell and angiogenesis in traumatic brain injury rats were antagonized by progesterone receptor antagonist.
作者信息
Yu Peng, Li Shengjie, Zhang Zhifei, Wen Xiaolong, Quan Wei, Tian Qilong, Gao Chuang, Su Wanqiang, Zhang Jianning, Jiang Rongcai
机构信息
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
Tianjin Neurological Institute, Tianjin, China.
出版信息
Cell Prolif. 2017 Oct;50(5). doi: 10.1111/cpr.12362. Epub 2017 Jul 28.
OBJECTIVES
Progesterone (P4) has the potential therapeutic effects for traumatic brain injury (TBI) whose recovery depended on the enhanced angiogenesis. Endothelial progenitor cell (EPC) plays an essential role in vascular biology. We previously demonstrated that P4 administration improved circulating EPC level and neurological recovery of rat with TBI. Here, we hypothesized that P4 augmented angiogenic potential of EPC and the angiogenesis-related neurorestoration after TBI through classical progesterone receptor (PR).
MATERIALS AND METHODS
EPC derived from rats were stimulated with graded concentrations (0, 10 , 10 , 5 × 10 , 10 , 10 mol/L) of P4 or 10 mol/L ulipristal acetate (UPA, a PR antagonist). Male rats were subjected to cortical impact injury and treated with (i) DMSO (dimethyl sulfoxide), (ii) P4 and (iii) P4 and UPA.
RESULTS
It showed that P4 improved the angiogenic potential of EPC, including tube formation, adhesion, migration and vascular endothelial growth factor secretion, in a dose-dependent fashion with the maximal effect achieved at 10 mol/L P4. High concentration (10 mol/L) of P4 impaired the angiogenic potential of EPC. Notably, 10 mol/L UPA antagonized the stimulatory effects of 10 mol/L P4. After administrating P4, a significant improvement of neurological function and the restoration of the leaked blood-brain barrier were observed as well as a reduction of the brain water content. Both vessel density and expression of occludin of vessels were increased. When UPA was administered with P4, the neural restoration and angiogenesis were all reversed. Western blot showed that 10 mol/L P4 increased the content of PRA and PRB of EPC, while 10 mol/L P4 reduced the content of both PR isoforms, but there was no change found in the TBI rats.
CONCLUSIONS
It may suggest that P4-mediated angiogenic activity of EPC and angiogenesis in TBI rats were antagonized by PR antagonist.
目的
孕酮（P4）对创伤性脑损伤（TBI）具有潜在治疗作用，其恢复依赖于增强的血管生成。内皮祖细胞（EPC）在血管生物学中起重要作用。我们之前证明，给予P4可提高TBI大鼠的循环EPC水平和神经功能恢复。在此，我们假设P4通过经典孕酮受体（PR）增强EPC的血管生成潜能以及TBI后的血管生成相关神经修复。
材料与方法
用不同浓度（0、10、10、5×10、10、10 mol/L）的P4或10 mol/L醋酸乌利司他（UPA，一种PR拮抗剂）刺激大鼠来源的EPC。雄性大鼠接受皮质撞击损伤，并分别用（i）二甲基亚砜（DMSO）、（ii）P4和（iii）P4与UPA进行治疗。
结果
结果显示，P4以剂量依赖方式改善EPC的血管生成潜能，包括管腔形成、黏附、迁移和血管内皮生长因子分泌，在10 mol/L P4时达到最大效应。高浓度（10 mol/L）的P4损害EPC的血管生成潜能。值得注意的是，10 mol/L UPA拮抗10 mol/L P4的刺激作用。给予P4后，观察到神经功能显著改善、血脑屏障渗漏恢复以及脑含水量降低。血管密度和血管紧密连接蛋白的表达均增加。当UPA与P4联合给药时，神经修复和血管生成均被逆转。蛋白质印迹法显示，10 mol/L P4增加EPC中PRA和PRB的含量，而10 mol/L UPA降低两种PR亚型的含量，但TBI大鼠中未发现变化。
结论
这可能表明PR拮抗剂拮抗了P4介导的TBI大鼠EPC血管生成活性和血管生成。
Zotero 插件