Abstract
Recent studies from our laboratory have suggested the potent AMP kinase (AMPK) activator 5‐aminimidazole‐4‐carboxamide‐3‐ ribnucleotide (AICAR) lowers blood pressure and restores angiogenic balance (e.g. increased ratio of VEGF (vascular endothelial growth factor) to sFlt‐1 (soluble VEGF receptor 1) in rats with placental ischemia‐induced hypertension, but the mechanisms remain unknown. The purpose of this study was to model placental ischemia with human placental trophoblast (BeWo) and umbilical vascular endothelial (HUVEC) cells, and determine if AICAR modifies angiogenic balance via adenosine receptor or adenosine transporter mediated mechanisms. Cells were cultured at 37°C for 12 hours in atmospheric (20%), physiologic normoxic (8%) or hypoxic (1.5%) conditions, and treated with AICAR (2mM), purinergic (P1) receptor (8‐(p‐sulfophenyl) theophylline, 8‐SPT) and adenosine transporter (dipyridamole, DPM) blockers (100μM). HUVECs treated with AICAR showed a decreased (P<0.05) secreted sFlt‐1 in all O2 conditions, and DPM blocked this effect and not by 8‐SPT. AMPKα phosphorylation was increased (P<0.05) in hypoxic HUVECs with AICAR, and DPM blocked this effect. BeWos were unaffected by AICAR. Through modeling placental ischemia in vitro, we have demonstrated AICAR decreases sFlt‐1 secretion by HUVECs and this is mediated by increased intracellular AICAR and not via P1 receptor signaling.
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