Hirschi 2019 Biol Reprod
|Hirschi KM, Tsai KYF, Davis T, Clark JC, Knowlton MN, Bikman BT, Reynolds PR, Arroyo JA (2019) Growth arrest specific protein (Gas)-6/AXL signaling induces preeclampsia (PE) in rats. Biol Reprod [Epub ahead of print].|
Abstract: 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 3 groups that received daily intraperitoneal injections (from gestational day 7.5-17.5) of PBS, Gas6, or Gas6 + R428 (an AXL inhibitor administered from gestational day 13.5-17.5). 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 were 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.
© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Other
Organism: Rat Tissue;cell: Genital Preparation: Permeabilized cells, Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS HRR: Oxygraph-2k