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.

Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface

“…In the most severely affected patients, immunolocalization on tissue sections of the placenta showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; however, staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 (sFlt-1) in vitro also increased (116), an observation that gains additional importance in light of the recent discovery that excess sFlt-1 produces a preeclampsia-like syndrome in rats (123). However, it is important to note that preeclampsia has a very complex etiology and an equally complex constellation of placental effects.…”

What determines glomerular capillary permeability?

“…The endothelium has often been viewed as an insignificant part of the barrier, but this interpretation seems unjustified. That Θ en ≪1 for albumin is suggested by tracer visualization studies (11) and by the proteinuria that accompanies preeclampsia, which selectively affects the endothelium (12). The fenestrae themselves are too large to effectively sieve macromolecules, which suggests that the barrier properties of the endothelium are derived from the cell coat, or glycocalyx, that fills the fenestrae and extends into the capillary lumen.…”

Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered?

“…In this issue of the JCI, S.E. Maynard et al (4) report the novel insight that circulating levels of two angiogenic growth factors, VEGF and placental growth factor (PlGF), may play a more important role than previously believed. In particular, the authors propose that, in pregnant women with preeclampsia, the placenta produces elevated levels of the soluble fms-like tyrosine kinase 1 (sFlt1) receptor, which captures free VEGF and PlGF.…”