Department of Animal and Range Sciences, New Mexico State University, Las Cruces, NM 88003, USA.
Department of Animal Sciences, Center for Nutrition and Pregnancy, North Dakota State University, Fargo, ND 58108, USA.
Domest Anim Endocrinol. 2014 Apr;47:11-21. doi: 10.1016/j.domaniend.2013.12.004. Epub 2014 Jan 7.
Early pregnancy, when most embryonic losses occur, is a critical period in which vital placental vascularization is established. Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis, and factors that regulate VEGF function, expression, or both may ultimately affect vascularization. Activation of the C-X-C chemokine receptor type 4 (CXCR4) by its cognate ligand, C-X-C chemokine ligand 12 (CXCL12), increases VEGF synthesis and secretion, which in turn stimulates CXCL12 and CXCR4 production and this synergistic regulation may influence placental vascularization. We hypothesized that expression of CXCL12, CXCR4, select angiogenic factors, and their receptors would increase in placental tissues during early pregnancy and that treatment of ovine trophectoderm cells with CXCL12 would increase production of angiogenic factors. To test this hypothesis, maternal caruncle (CAR) and fetal extraembryonic membrane (FM) tissues were collected on days 18, 20, 22, 25, 26, and 30 of pregnancy and on day 10 of the estrous cycle (control, NP) to determine relative mRNA or protein expression of CXCL12 and CXCR4 and selected angiogenic factors. In CAR, expression of mRNA for CXCR4 increased on day 18, 20, 22, and 25 and CXCL12 increased on day 18 and 20 compared with NP ewes. CXCL12 protein followed a similar pattern in CAR tissue, with greater levels on day 20 than in NP tissue. Greater levels of fibroblast growth factor 2 (FGF2) mRNA was observed in CAR on day 20 of gestation than on day 30. In FM, CXCL12, CXCR4, angiopoietin 1, VEGF, and VEGF receptor 1 were enhanced with advancing pregnancy, whereas FGF2 and kinase insert domain receptor (or VEGF receptor 2) peaked on day 25. An increase in protein levels occurred on day 25 compared with day 20 in FM for CXCL12 and CXCR4, as well as a similar tendency for FGF2 protein. Both CXCL12 and CXCR4 are specifically localized to trophoblast cells and to the uterine luminal and glandular epithelium. Treatment of ovine trophectoderm cells with CXCL12 increased mRNA expression for VEGF and FGF2. The relationship between VEGF, FGF2, and the CXCL12/CXCR4 signaling underscores the potential role for this chemokine axis in driving placentation.
早期妊娠是胚胎丢失发生的关键时期，在此期间，重要的胎盘血管生成得以建立。血管内皮生长因子（VEGF）是血管生成的有效诱导剂，调节 VEGF 功能、表达或两者的因素最终可能会影响血管生成。其同源配体 C-X-C 趋化因子配体 12（CXCL12）激活 C-X-C 趋化因子受体 4（CXCR4），增加 VEGF 的合成和分泌，反过来又刺激 CXCL12 和 CXCR4 的产生，这种协同调节可能影响胎盘血管生成。我们假设在妊娠早期胎盘组织中 CXCL12、CXCR4、选择的血管生成因子及其受体的表达会增加，并且用 CXCL12 处理绵羊滋养层细胞会增加血管生成因子的产生。为了验证这一假设，在妊娠第 18、20、22、25、26 和 30 天和发情周期第 10 天（对照，NP）采集母体胎盘（CAR）和胎儿外胚膜（FM）组织，以确定 CXCL12 和 CXCR4 及选择的血管生成因子的相对 mRNA 或蛋白表达。在 CAR 中，与 NP 母羊相比，CXCR4 的 mRNA 表达在第 18、20、22 和 25 天增加，而 CXCL12 在第 18 和 20 天增加。CAR 组织中的 CXCL12 蛋白也呈现出类似的模式，第 20 天的水平高于 NP 组织。妊娠第 20 天 CAR 中纤维母细胞生长因子 2（FGF2）的 mRNA 水平高于第 30 天。在 FM 中，随着妊娠的进展，CXCL12、CXCR4、血管生成素 1、VEGF 和 VEGF 受体 1 增加，而 FGF2 和激酶插入结构域受体（或 VEGF 受体 2）在第 25 天达到峰值。与第 20 天相比，FM 中 CXCL12 和 CXCR4 的蛋白水平在第 25 天增加，FGF2 蛋白也呈现出类似的趋势。CXCL12 和 CXCR4 均特异性定位于滋养层细胞和子宫腔和腺上皮。用 CXCL12 处理绵羊滋养层细胞可增加 VEGF 和 FGF2 的 mRNA 表达。VEGF、FGF2 和 CXCL12/CXCR4 信号之间的关系突出了这种趋化因子轴在驱动胎盘形成中的潜在作用。
