Angiogenic Response of Placental Villi to Heparin

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OBJECTIVE:To estimate the angiogenic effect of heparin on human umbilical vein endothelial cells cultured in conditioned media from normal and severely pre-eclamptic human placental villi.METHODS:Normal first- and second-trimester floating placental villi were explanted in control conditions and increasing concentrations of heparin (unfractionated and low molecular weight heparin) across the clinical prophylactic and therapeutic range (0.025–25 units/mL). At 96 hours, the placenta-conditioned media was tested for angiogenic activity in a human umbilical vein endothelial cell in vitro angiogenesis assay. Total capillary-like tube length and number of branch points were determined from photographs that did not contain information about experimental conditions. The response of placenta-conditioned media from preterm severely preeclamptic pregnant women exposed to low molecular weight heparin also was assessed and compared with both preterm and term control groups.RESULTS:Unfractionated heparin significantly promoted angiogenesis (0.25 units/mL compared with control: relative branch points 185±32% [mean±standard error of the mean], P<.05), whereas low molecular weight heparin had no significant effect. Addition of unfractionated or low molecular weight heparin to first- and second-trimester placenta-conditioned media significantly promoted angiogenesis with the response to low molecular weight heparin more than double that of unfractionated heparin (low molecular weight compared with unfractionated heparin at 2.5 units/mL: relative branch points 930±158% compared with 398±90%, P<.05). Placenta-conditioned media from pregnancies with severe preeclampsia arrested angiogenesis in comparison with both preterm and term pregnancies and was not significantly restored by the addition of low molecular weight heparin.CONCLUSION:Unfractionated and low molecular weight heparin promote in vitro angiogenesis in healthy first- and second-trimester placenta-conditioned media. The nonanticoagulant actions of heparin may be relevant to the prevention of severe preeclampsia.

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