Department of Animal and Range Sciences, New Mexico State University, Las Cruces, New Mexico, USA.
Biol Reprod. 2019 Jul 1;101(1):102-111. doi: 10.1093/biolre/ioz073.
Placenta development is characterized by extensive angiogenesis and vascularization but if these processes are compromised placental dysfunction occurs, which is the underlying cause of pregnancy complications such as preeclampsia and intrauterine growth restriction. Dysregulation of placental angiogenesis has emerged as one of the main pathophysiological features in the development of placental insufficiency and its clinical consequences. The signaling axis initiated by chemokine ligand 12 (CXCL12) and its receptor CXCR4 stimulates angiogenesis in other tissues, and may be central to placental vascularization. We hypothesized that CXCL12-CXCR4 signaling governs the pro-angiogenic placental microenvironment by coordinating production of central angiogenic factors and receptors and regulates endometrial cell survival essential for placental function and subsequent fetal longevity. The CXCR4 antagonist, AMD3100, was used to elucidate the role of CXCL12-CXCR4 signaling regarding uteroplacental vascular remodeling at the fetal-maternal interface. On day 12 postbreeding, osmotic pumps were surgically installed and delivered either AMD3100 or PBS into the uterine lumen ipsilateral to the corpus luteum. On day 20, endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections preserved for immunofluorescent analysis. In endometrium from ewes receiving AMD3100 infusion, the abundance of select angiogenic factors was diminished, while presence of CD34+ cells increased compared to control ewes. Ewes receiving AMD3100 infusion also exhibited less activation of Akt/mTOR signaling, and elevated LC3B-II, a marker of cellular autophagy in endometrium. This study suggests that CXCL12-CXCR4 signaling governs placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.
胎盘发育的特征是广泛的血管生成和血管化，但如果这些过程受到损害，就会发生胎盘功能障碍，这是子痫前期和宫内生长受限等妊娠并发症的根本原因。胎盘血管生成的失调已成为胎盘功能不全及其临床后果的主要病理生理特征之一。趋化因子配体 12 (CXCL12)及其受体 CXCR4 启动的信号轴刺激其他组织的血管生成，并且可能是胎盘血管化的核心。我们假设 CXCL12-CXCR4 信号通过协调中央血管生成因子和受体的产生来调节胎盘的促血管生成微环境，并调节子宫内膜细胞的存活，这对于胎盘功能和随后的胎儿长寿至关重要。使用 CXCR4 拮抗剂 AMD3100 阐明了 CXCL12-CXCR4 信号在胎儿-母体界面调节胎盘血管重塑中的作用。在配种后第 12 天，通过手术将渗透泵植入并将 AMD3100 或 PBS 递送到黄体同侧的子宫腔中。在第 20 天，收集子宫内膜组织，液氮中冷冻，并保存子宫角切片进行免疫荧光分析。在接受 AMD3100 输注的母羊的子宫内膜中，选择的血管生成因子的丰度减少，而与对照母羊相比，CD34+细胞的存在增加。接受 AMD3100 输注的母羊的 Akt/mTOR 信号也表现出较少的激活，并且子宫内膜中细胞自噬的标志物 LC3B-II 升高。这项研究表明，CXCL12-CXCR4 信号通过作为血管生成和细胞活力的关键上游调节剂来调节胎盘稳态，从而确保适当的胎盘发育。
