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 6

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sFlt1 induces glomerular endotheliosis. (a) Histopathological analysis o...
sFlt1 induces glomerular endotheliosis. (a) Histopathological analysis of renal tissue from one representative Fc-treated pregnant rat (upper panel), one sFlt1–treated pregnant rat (middle panel), and one sFlk1-Fc–treated pregnant rat (lower panel) is shown here. H&E stain shows capillary occlusion in the sFlt1 treated animal with enlarged glomeruli and swollen endothelial cells compared to Fc control animal and sFlk1-Fc control animals. PAS stain of the sFlt1–treated rat demonstrates PAS-negative swollen cytoplasm of endocapillary cells (endotheliosis). Numerous protein resorption droplets are also seen in the PAS section. These pathologic changes are absent in the Fc-treated rat as well as the sFlk1-Fc–treated pregnant rats. All light photomicrographs were taken at ×60 (original magnification). (b) Electron microscopy (EM) and immunofluorescence (IF) for fibrin was performed for the same rats shown in Figure 6a. Electron micrographs of glomeruli from an sFlt1–treated rat (lower panel) confirmed cytoplasmic swelling of the endocapillary cells. There is relative preservation of the podocyte foot processes and the basement membranes. Immunofluorescence for fibrin shows foci of fibrin deposition within the glomeruli of sFlt1–treated rats but not Fc-treated rats. The immunofluorescence pictures were taken at ×40 and the electron micrographs were taken at ×2400 (original magnification). All figures are reproduced at identical magnifications. (c) Histopathological analysis of one representative nonpregnant rat treated with low-dose sFlt1 is shown here. Low-power (×30, original magnification) Masson trichrome staining of renal tissue from the low-dose sFlt1–treated rat shows varying glomerular size representing focal endotheliosis. This degree of variation in glomerular involvement was only noted in the low-dose group. Higher-power H&E staining and PAS staining showed segmental endotheliosis and protein resorption droplets with preservation of basement membranes.