Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model

Abstract

One driving factor for developing preeclampsia—a pregnancy disorder, often associated with poor spiral artery (SpA)-remodeling and fetal growth restriction—is the anti-angiogenic sFLT1 (soluble fms-like tyrosine kinase-1), which is found to be highly upregulated in preeclampsia patients. The sFLT1-mediated endothelial dysfunction is a common theory for the manifestation of maternal preeclampsia symptoms. However, the influence of sFLT1 on SpA-remodeling and the link between placental and maternal preeclampsia symptoms is less understood. To dissect the hsFLT1 (human sFLT1) effects on maternal and/or fetoplacental physiology in preeclampsia, sFLT1-transgenic mice with systemic hsFLT1 overexpression from midgestation onwards were used. SpA-remodeling was analyzed on histological and molecular level in placental/mesometrial triangle tissues. Maternal kidney and aorta morphology was investigated, combined with blood pressure measurements via telemetry. hsFLT1 overexpression resulted in maternal hypertension, aortic wall thickening, and elastin breakdown. Furthermore, maternal kidneys showed glomerular endotheliosis, podocyte damage, and proteinuria. preeclampsia symptoms were combined with fetal growth restriction already at the end of the second trimester and SpA-remodeling was strongly impaired as shown by persisted vascular smooth muscle cells. This phenotype was associated with shallow trophoblast invasion, delayed presence of uterine natural killer cells, and altered lymphatic angiogenesis. Overall, this study showed that circulating maternal hsFLT1 is sufficient to induce typical maternal preeclampsia-like symptoms in mice and impair the SpA-remodeling independent from the fetoplacental compartment, revealing new insights into the interaction between the placental and maternal contribution of preeclampsia.

Systemic Maternal Human sFLT1 Overexpression Leads to an Impaired Foetal Brain Development of Growth-Restricted Foetuses upon Experimental Preeclampsia

“…Our own previous work using an experimental transgenic human sFLT1- (hsFLT1-) related PE/FGR mouse model clearly showed that elevated hsFLT1 levels in maternal circulation resulted in placental dysfunction characterized by increased placental hypoxia, shown by an increase in hypoxia-inducible factors ( Hif1α , Hif2α ), leading to foetal growth restriction already starting at the end of the second trimester during pregnancy with viable and nonviable foetuses. Our previous results supported the hypothesis that this was due to reduced uteroplacental vascularization including impaired spiral arterial remodelling and foetal vessel development in the placental labyrinth [ 11 , 12 ].…”

“…Taking into account that human sFLT1 (hsFLT1) overexpression revealed a negative impact on fetoplacental [ 11 ] and uteroplacental vascularization [ 12 ] as well as foetal body weight gain during pregnancy [ 11 , 12 ] in our hsFLT1-transgenic PE mouse model, we conjectured that systemic hsFLT1 overexpression impairs foetal neurodevelopment during pregnancy due to undernutrition and underperfusion of the placenta and foetus and thereby might promote long-lasting neurodevelopmental deficits in PE offspring independent of prematurity.…”

Evidence from human placenta, ER-stressed trophoblasts and transgenic mice links transthyretin proteinopathy to preeclampsia

“…Since numerous prior studies have shown that higher serum levels of sFlt-1 and sEng contribute to the pathogenesis of PE 19, 20, 22, 23 , we measured the concentration of these anti-angiogenic factors using respective ELISA kits. The analysis showed significantly higher levels of sFlt-1 and sEng in the sera from pregnant huTTR mice when compared with age-matched pregnant wild-type mice (Figure 5E and F).…”

Animal Models of Cardiovascular Complications of Pregnancy

“…Transgenic or adenoviral overexpression of sFLT1 alone or in combination with sENG develops more robust preeclampsia phenotypes, including severe hypertension, nephrotic range proteinuria, cerebral edema, and HELLP like phenotypes. [41][42][43]95 Taken together with the data that, in humans, high levels of sFLT1 and sENG correlate with adverse maternal and fetal outcomes, 20 there has been great interest in testing targeted therapies for preeclampsia in antiangiogenic overexpression model. A significant limitation of the rodent model, however, is lack of expression of all the isoforms of sFLT1 expressed in humans, 96 making it difficult to study molecular therapies such as antibodies that preferentially bind one isoform over others.…”