Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia
Sharon E. Maynard, … , Vikas P. Sukhatme, S. Ananth Karumanchi
Sharon E. Maynard, … , Vikas P. Sukhatme, S. Ananth Karumanchi
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):649-658. https://doi.org/10.1172/JCI17189.
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Article Nephrology

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Abstract

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

Authors

Sharon E. Maynard, Jiang-Yong Min, Jaime Merchan, Kee-Hak Lim, Jianyi Li, Susanta Mondal, Towia A. Libermann, James P. Morgan, Frank W. Sellke, Isaac E. Stillman, Franklin H. Epstein, Vikas P. Sukhatme, S. Ananth Karumanchi

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sFlt1 inhibits VEGF- and PlGF-induced vasodilation of renal microvessel....
sFlt1 inhibits VEGF- and PlGF-induced vasodilation of renal microvessel. (a) The relaxation responses of rat renal arterioles to sFlt1, VEGF, and PlGF at three different doses were measured. S, sFlt1; V, VEGF; P, PlGF. V+ and P+ represent responses to VEGF and PlGF in the presence of sFlt1 at 100 ng/ml. A positive change reflects an increase in vessel diameter. (b) Microvascular relaxation responses were measured at physiological doses of VEGF (100 pg/ml), PlGF (500 pg/ml), sFlt1 (10 ng/ml), VEGF (100 pg/ml) plus PlGF (500 pg/ml), or VEGF (100 pg/ml) plus PlGF (500 pg/ml) plus sFlt1 (10 ng/ml). Each experiment was repeated in six different rat renal microvessels, and data are reported as means ± SEM. *P < 0.05 as compared with VEGF plus PlGF. Reagents used for the assays were recombinant rat VEGF, mouse PlGF, and mouse sFlt1-Fc.