Ashley Ryan L, Runyan Cheyenne L, Maestas Marlie M, Trigo Elisa, Silver Gail
Department of Animal and Range Sciences, New Mexico State University, Las Cruces, NM, United States.
Front Vet Sci. 2021 Aug 16;8:650687. doi: 10.3389/fvets.2021.650687. eCollection 2021.
The placenta, a unique organ that only develops during pregnancy, is essential for nutrient, oxygen, and waste exchange between offspring and mother. Yet, despite its importance, the placenta remains one of the least understood organs and knowledge of early placental formation is particularly limited. Abnormalities in placental development result in placental dysfunction or insufficiency whereby normal placental physiology is impaired. Placental dysfunction is a frequent source of pregnancy loss in livestock, inflicting serious economic impact to producers. Though the underlying causes of placental dysfunction are not well-characterized, initiation of disease is thought to occur during establishment of functional fetal and placental circulation. A comprehensive understanding of the mechanisms controlling placental growth and vascularization is necessary to improve reproductive success in livestock. We propose chemokine C-X-C motif ligand 12 (CXCL12) signaling through its receptor CXCR4 functions as a chief coordinator of vascularization through direct actions on fetal trophoblast and maternal endometrial and immune cells. To investigate CXCL12-CXCR4 signaling on uteroplacental vascular remodeling at the fetal-maternal interface, we utilized a CXCR4 antagonist (AMD3100). On day 12 post-breeding in sheep, osmotic pumps were surgically installed and delivered either AMD3100 or saline into the uterine lumen ipsilateral to the corpus luteum for 14 days. On day 35 of ovine pregnancy, fetal/placental and endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections were preserved for immunofluorescent analysis. Suppressing CXCL12-CXCR4 at the fetal-maternal interface during initial placental vascularization resulted in diminished abundance of select angiogenic factors in fetal and maternal placenta on day 35. Compared to control, less vascular endothelial growth factor (VEGF) and VEFG receptor 2 (KDR) were observed in endometrium when CXCL12-CXCR4 was diminished. Less VEGF was also evident in fetal placenta (cotyledons) in ewes receiving AMD3100 infusion compared to control. Suppressing CXCL12-CXCR4 at the fetal-maternal interface also resulted in greater autophagy induction in fetal and maternal placenta compared to control, suggestive of CXCL12-CXCR4 impacting cell survival. CXCL12-CXCR4 signaling may govern placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.
胎盘是一种仅在孕期发育的独特器官，对胎儿与母体之间的营养、氧气及废物交换至关重要。然而，尽管其重要性不言而喻，但胎盘仍是人们了解最少的器官之一，关于胎盘早期形成的知识尤为有限。胎盘发育异常会导致胎盘功能障碍或功能不全，进而损害正常的胎盘生理功能。胎盘功能障碍是家畜妊娠丢失的常见原因，给养殖户造成严重的经济影响。尽管胎盘功能障碍的潜在原因尚未完全明确，但疾病的起始被认为发生在功能性胎儿和胎盘循环建立期间。全面了解控制胎盘生长和血管生成的机制对于提高家畜繁殖成功率至关重要。我们提出趋化因子C-X-C基序配体12（CXCL12）通过其受体CXCR4发出的信号，通过对胎儿滋养层细胞、母体子宫内膜细胞和免疫细胞的直接作用，作为血管生成的主要协调因子发挥作用。为了研究CXCL12-CXCR4信号对胎儿-母体界面子宫胎盘血管重塑的影响，我们使用了CXCR4拮抗剂（AMD3100）。在绵羊配种后第12天，通过手术植入渗透泵，将AMD3100或生理盐水注入黄体同侧的子宫腔，持续14天。在绵羊妊娠第35天，收集胎儿/胎盘和子宫内膜组织，在液氮中速冻，保留子宫角横断面用于免疫荧光分析。在胎盘血管生成初期抑制胎儿-母体界面的CXCL12-CXCR4信号，会导致妊娠第35天时胎儿和母体胎盘中某些血管生成因子的丰度降低。与对照组相比，当CXCL12-CXCR4信号被减弱时，子宫内膜中观察到的血管内皮生长因子（VEGF）和VEGF受体2（KDR）减少。与对照组相比，接受AMD3100输注的母羊胎儿胎盘（子叶）中VEGF也明显减少。与对照组相比，在胎儿-母体界面抑制CXCL12-CXCR4信号还会导致胎儿和母体胎盘中自噬诱导增加，提示CXCL12-CXCR4影响细胞存活。CXCL12-CXCR4信号可能通过作为血管生成和细胞活力的关键上游调节因子来维持胎盘内环境稳定，从而确保胎盘正常发育。
