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21: Placental ischemia triggers immune activation as leukocyte overproduction of SFLT-1: a step in the pathogenesis of preeclampsia?

      Objective

      Plasma, amniotic fluid, and placental soluble fms-like tyrosine kinase (sFlt-1) mRNA is increased in patients with preeclampsia. Leukocytosis frequently accompanies the onset of HELLP syndrome. Investigators, including the ones at our lab, have shown placental ischemia (PI), circulating TNF alpha and agonistic auto-antibodies to the angiotensin II type I receptor to be important stimuli for sFlt-1 production during pregnancy. These studies suggest that immune activation in response to PI may play a role in sFlt-1 production. The objective of this study was to determine if leukocytes stimulated in rats with PI are a source of circulating sFlt-1.

      Study Design

      Sprague-Dawley rats were anesthetized on day 14 of pregnancy and underwent either examination under anesthesia (NP) or reduced uterine perfusion pressure (RUPP) in which the lower abdominal aorta above the iliac bifurcation (0.203mm ID clip) and both ovarian arteries (0.100mm ID clip) were isolated and chronically constricted. Rats were instrumented with a carotid catheter for arterial pressure measurement (MAP) on day 19. Plasma was collected in EDTA and leukocytes were isolated utilizing Lymphoprep centrifugation technique. Leukocytes were cultured overnight in RPMI media containing, 1.022 ng/ml IL-2 and 4 ng/ml IL-12 at 5% CO2 and 37°C. Cell culture media was removed and utilized in ELISA to determine sFlt-1.

      Results

      MAP increased from 102 +/− 1 mmHg in NP rats to 127 +/− 2 mmHg in response to PI in RUPP rats. Circulating sFlt-1 was 963 pg/ml in NP rats vs. 1493 pg/ml in RUPP rats. In addition, sFlt-1 from NP PBL culture was 30+/−8 pg/ml. SFlt-1 from RUPP PBL culture increased significantly to 88+/−20 pg/ml (P <0.01).

      Conclusion

      The mechanisms whereby sFlt-1 over expression occurs during preeclampsia are not well defined. This study demonstrates that immune cells are activated during hypertension in response to PI to be a source for excess sFlt-1.