Lung and Placenta Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.
Laboratory of Obesity and Metabolism, Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.
Biol Reprod. 2020 Feb 12;102(1):199-210. doi: 10.1093/biolre/ioz140.
Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure, decreased trophoblast invasion, and inflammation. The growth arrest-specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. Gas6 binds to the AXL tyrosine kinase receptor and AXL-mediated signaling is implicated in proliferation and migration observed in several tissues. Our laboratory utilized Gas6 to induce preeclamptic-like conditions in pregnant rats. Our objective was to determine the role of Gas6/AXL signaling as a possible model of PE. Briefly, pregnant rats were divided into three groups that received daily intraperitoneal injections (from gestational day 7.5 to 17.5) of phosphate buffered saline (PBS), Gas6, or Gas6 + R428 (an AXL inhibitor administered from gestational day 13.5 to 17.5). Animals dispensed Gas6 experienced elevated blood pressure, increased proteinuria, augmented caspase-3-mediated placental apoptosis, and diminished trophoblast invasion. Gas6 also enhanced expression of several PE-related genes and a number of inflammatory mediators. Gas6 further enhanced placental oxidative stress and impaired mitochondrial respiration. Each of these PE-related characteristics was ameliorated in dams and/or their placentae when AXL inhibition by R428 occurred in tandem with Gas6 treatment. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL prevents disease progression in pregnant rats. These results provide insight into pathways associated with PE that could be useful in the clarification of potential therapeutic approaches.
子痫前期（PE）是一种复杂的产科并发症，其特征为血压升高、滋养细胞侵袭减少和炎症。生长停滞特异性基因 6（Gas6）蛋白可诱导动态细胞反应，在 PE 中升高。Gas6 与 AXL 酪氨酸激酶受体结合，AXL 介导的信号转导与几种组织中观察到的增殖和迁移有关。我们实验室利用 Gas6 在怀孕大鼠中诱导子痫前期样条件。我们的目的是确定 Gas6/AXL 信号作为 PE 可能模型的作用。简而言之，怀孕大鼠分为三组，每天接受腹腔注射（从妊娠第 7.5 天到 17.5 天）磷酸盐缓冲盐水（PBS）、Gas6 或 Gas6+R428（AXL 抑制剂，从妊娠第 13.5 天到 17.5 天给药）。接受 Gas6 处理的动物血压升高、蛋白尿增加、半胱氨酸天冬氨酸蛋白酶-3 介导的胎盘细胞凋亡增加、滋养细胞侵袭减少。Gas6 还增强了几种与 PE 相关的基因和许多炎症介质的表达。Gas6 进一步增强了胎盘的氧化应激和线粒体呼吸受损。当 R428 与 Gas6 治疗同时抑制 AXL 时，母鼠及其胎盘均可改善这些与 PE 相关的特征。我们得出结论，Gas6 信号能够诱导 PE，并且 AXL 抑制可防止怀孕大鼠的疾病进展。这些结果提供了与 PE 相关的途径的见解，这可能有助于阐明潜在的治疗方法。
