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Activation of AXL Receptor via Gas6 induces Preeclampsia in Rats
Author(s) -
Dunaway Todd M,
Lewis Joshua B,
Hirschi Kelsey M,
Mejia Camilo A,
Mejia Juan F,
Hall Parker D,
Reynolds Paul R,
Arroyo Juan A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.978.17
Subject(s) - gas6 , preeclampsia , endocrinology , bronchoalveolar lavage , placentation , medicine , trophoblast , axl receptor tyrosine kinase , receptor tyrosine kinase , fetus , biology , tyrosine kinase , receptor , andrology , placenta , lung , pregnancy , jak stat signaling pathway , genetics
Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure and decreased trophoblast invasion. The growth arrest‐specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. This discovery suggests a mechanistic role for the Gas6 signaling pathway during PE progression. Gas6 binds to the AXL tyrosine kinase receptor and AXL‐mediated signaling is implicated in proliferation and migratory mechanisms in several tissues. Our objective was to determine the role of Gas6 and AXL signaling in the development of PE in the rat. We utilized Gas6 to induce preeclamptic conditions in pregnant rats. Briefly, pregnant rats were divided into 3 groups that received daily ip injections of PBS, Gas6, or Gas6 + R428 (an AXL inhibitor). Treatment was done from embryonic day 7.5 (E7.5) to E18.5, at which time they were euthanized and tissues were harvested for histological and molecular characterization. Fetal and placental weights were recorded. Blood pressure, proteinuria and cell invasion was determined. We additionally characterized inflammatory conditions in the maternal lung due to links between respiratory sufficiency, placentation, and fetal health. Bronchoalveolar lavage fluid (BALF) was procured from maternal lungs for the assessment of inflammatory cells and cytokine secretion. Western blot was performed to determine AXL protein expression. We observed: increased proteinuria and elevated blood pressure in Gas6 treated animals, but each were inhibited by R428; placental and fetal weights revealed no significant changes among groups; immunohistochemical analysis revealed decreased trophoblast invasion in animals treated with Gas6. BALF revealed elevated cell diapedesis in Gas6 animals, which was absent in animals given R428. Quantitative RT‐PCR and immunoblotting revealed increased expression of RAGE (a pattern recognition receptor implicated in inflammation), AXL, and pro‐inflammatory cytokines TNF‐α and IL‐1β. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL receptor prevents disease progression in pregnant rats. These data suggest roles for Gas6/AXL in the development of PE and offer possible treatment avenues that could help in alleviating PE symptoms.