The Effect of Immune Factors, Tumor Necrosis Factor-α, and Agonistic Autoantibodies to the Angiotensin II Type I Receptor on Soluble fms-Like Tyrosine-1 and Soluble Endoglin Production in Response to Hypertension During Pregnancy


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Abstract

BackgroundPreeclampsia is considered a disease of immunological origin associated with abnormalities in inflammatory cytokines, tumor necrosis factor-α (TNF-α), and activated lymphocytes secreting autoantibodies to the angiotensin II receptor (AT1-AA). Recent studies have also demonstrated that an imbalance of angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1), and sEndoglin, exists in preeclampsia; however, the mechanisms that initiate their overproduction are unclear.MethodsTo determine the role of immune regulation of these factors, circulating and placental sFlt-1 and/or sEndoglin was examined from pregnant rats chronically treated with TNF-α or AT1-AA. On day 19 of gestation blood pressure was analyzed and serum and tissues were collected. Placental villous explants were excised and cultured on matrigel coated inserts for 24h and sFlt-1 and sEndoglin was measured from media.ResultsIn response to TNF-α-induced hypertension, sFlt-1 increased from 180 ± 5 to 2,907 ± 412pg/ml. sFlt-1 was also increased from cultured placental explants of TNF-α induced hypertensive pregnant rats (n = 12) (2,544 ± 1,132pg/ml) vs. explants from normal pregnant (NP) rats (n = 12) (2,189 ± 586pg/ml) where as sEng was undetectable. Circulating sFlt-1 increased from 245 ± 38 to 3,920 ± 798pg/ml in response to AT1-AA induced hypertension. sFlt-1 levels were higher (3,400 ± 350 vs. 2,480 ± 900pg/ml) in placental explants from AT1-AA infused rats (n = 12) than NP rats (n = 7). In addition, sEndoglin increased from 30 ± 2.7 to 44 ± 3.3pg/ml (P < 0.047) in AT1-AA infused rats but was undetectable in the media of the placental explants.ConclusionsThese data suggest that immune factors may serve as an important stimulus for both sFlt-1 and sEndoglin production in response to placental ischemia.

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