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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/C440    most recent 00593.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bainbridge, S. A. Articles by Hubel, C. A. PubMed PubMed Citation Articles by Bainbridge, S. A. Articles by Hubel, C. A.

VASCULAR BIOLOGY

Uric acid attenuates trophoblast invasion and integration into endothelial cell monolayers

¹Magee-Womens Research Institute; ²Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine; ³Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh; ⁴Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 21 November 2008 ; accepted in final form 15 June 2009

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.

HTR-8/SVneo cells; vascular endothelium; placenta; spiral artery; preeclampsia