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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Figure 1

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mRNA and protein expression of sFlt1 in preeclampsia. (a) mRNA expressio...
mRNA and protein expression of sFlt1 in preeclampsia. (a) mRNA expression of placental sFlt1 from three patients with preeclampsia (P1, P2, and P3) and three normotensive term pregnancies (N1, N2, and N3) were determined by Northern blot analysis. The higher band (7.5 kb) is the full-length Flt1 mRNA, and the lower, more abundant band (3.4 kb) is the alternatively spliced sFlt1 mRNA. GAPDH is included as a loading control, and the location of 28S is indicated by an arrowhead. Patients P1 and P2 had severe preeclampsia, whereas patient P3 had mild preeclampsia. (b) ELISA was performed for sFlt1 on serum from patients with mild preeclampsia (PE), severe preeclampsia and from normotensive pregnant women at term (normal) as described in Table 1. Patients with preterm deliveries were included as additional controls to rule out changes due to gestational age. The numbers of patients tested are shown in parentheses on the x-axis. Serum samples were collected before delivery (t = 0) and 48 hours after delivery (t = 48). *P < 0.05 and **P < 0.01 as compared with normotensive controls.