Abstract 48: Hypoxia-induced Heparanse Regulates sFlt-1 Release from Placental Chorionic Villi
Preeclampsia is one of the most pervasive and serious complications of pregnancy in the US and worldwide, which currently has no effective pharmacological intervention. While the underlying cause of the disorder remains unclear, it is generally accepted that placental hypoperfusion leads to placental ischemia. In response pathogenic factors are produced by the placenta and secreted into the maternal circulation, leading to the maternal symptomatic phase of the disorder. One of the factors which has received a great deal of attention is the soluble VEGF receptor/antagonist sFlt-1, which is sufficient to produce maternal hypertension and is believed to be a major contributor to maternal endothelial dysfunction. The factors which regulate sFlt-1 secretion from the placenta are unclear, however recent evidence has shown that in normal pregnancy, localization of sFlt-1 (i.e. retained in the placenta vs. secretion into the circulation) is controlled by binding to extracellular heparan in the placenta. Here we have examined the effect of placental ischemia on the production and activity of heparanase, which can cleave extracellular heparan and release the locally retained sFlt-1. In response to placental ischemia, placental heparanase expression is increased ∼50% (1±0.03 vs 1.49±0.07 normalized expression, p<0.05) a result which is supported by in vitro experiments demonstrating a ∼2-fold increase (1±0.07 vs 2.02±0.3 normalized units, p<0.05) in secreted heparanase by chorionic villus explants cultured under hypoxic conditions. Continuous infusion of heparin, which can mimic heparanase by displacing sFlt-1 bound to extracellular heparan, displaces sFlt-1 from the placenta (913±33 vs 762±48 pg/ml, p<0.05), decreasing the bioavailable VEGF in the maternal circulation (1174±62 vs 1174±38 pg/ml, p<0.05). This is accompanied by a significant (10mmHg, p<0.05) increase in mean arterial pressure. Together, these results suggest an important role for heparan binding and heparanase expression in the control of sFlt-1 secretion from the ischemic placenta, and suggest a potential new therapeutic approach for the management of hypertension in preeclampsia.
- © 2012 by American Heart Association, Inc.