Uric Acid Attenuates Trophoblast Invasion and Integration into Endothelial Cell Monolayers

Hyperuricemia develops as early as 10 wk of gestation in women who later develop preeclampsia. At this time the invasive trophoblast cells are actively remodeling the uterine spiral arterioles, integrating into and finally replacing the vascular endothelial lining. In the nonpregnant population uric acid has several pathogenic effects on vascular endothelium. We therefore sought to examine the effects of uric acid (0-7 mg/dl) on trophoblast cell invasion through an extracellular matrix using an in vitro Matrigel invasion assay. We also assessed trophoblast integration into a uterine microvascular endothelial cell monolayer in a trophoblast-endothelial cell coculture model. Additionally, we addressed the importance of redox signaling and trophoblast-induced endothelial cell apoptosis. Uric acid elicited a concentration-dependent attenuation of trophoblast invasion and integration into a uterine microvascular endothelial cell monolayer. The attenuated trophoblast integration appeared to be the result of reduced trophoblast-induced endothelial cell apoptosis, likely through the intracellular antioxidant actions of uric acid. In a test of relevance, pooled serum (5% vol/vol) from preeclamptic women attenuated the ability of trophoblast cells to integrate into the endothelial cell monolayers compared with pooled serum from healthy pregnant controls, and this response was partially rescued when endogenous uric acid was previously removed with uricase. Taken together these data support the hypothesis that elevations in circulating uric acid in preeclamptic women contribute to the pathogenesis of the disorder, in part, through attenuation of normal trophoblast invasion and spiral artery vascular remodeling.