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.
Preeclampsia is a potentially life-threatening multisystem disease affecting 4% to 8% of pregnant women after the 20th week of gestation. An excess of placental expressed antiangiogenic soluble VEGF (vascular endothelial growth factor)-receptor 1 (soluble FMS-like tyrosine kinase 1) scavenges VEGF and PlGF (placental growth factor), causing generalized endothelial dysfunction. Interventions to restore the angiogenic balance in preeclamptic pregnancies are intensively studied and improve maternal and neonatal outcomes. Especially extracorporeal strategies to remove sFlt-1 are promising in human pregnancy. However, available apheresis systems adsorb sFlt-1 unspecifically and with low efficiency. Affinity-enhanced ligands are needed to improve performance and compatibility of apheresis treatments. Using computerized molecular modeling, we developed multimeric VEGF molecules comprised of single-chain VEGF
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dimers (scVEGF
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). A short peptide linker hampers intrachain dimerization to induce assembly preferably as tetrameric molecules as visualized in negative staining electron microscopy. scVEGF
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multimers possess 1.2-fold higher affinity for sFlt-1 as compared to the available antibodies or monomeric VEGF. Consequently, scVEGF multimers have the ability to competitively release sFlt-1 bound PlGF and, in particular, VEGF. In ex vivo adsorption experiments using serum samples from patients with preeclampsia, scVEGF multimers reduce sFlt-1 levels by 85% and increase PlGF and VEGF levels by 20- and 9-fold, respectively. Finally, performance and stability of sFlt-1 capturing scVEGF
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multimers were scrutinized on different matrices of which biocompatible agarose matrix yielded optimal results. We introduce the first VEGF-based highly efficient sFlt-1 apheresis system that is directly applicable in vivo due to utilization of inert agarose matrix, using a homomultimeric form of VEGF
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to restore the angiogenic balance in preeclampsia.
Objectives: The aim of this research is to study the complications of pregnancy associated with anencephaly. Study Methods: Thirty-five mothers who delivered an anencephalic baby (as a case group) and forty-three mothers who delivered a non-anencephalic baby (as a control group)were included in this analytical research study. All cases and controls had singleton pregnancies. More than one matched control was chosen for each case when possible. The cases were selected by a survey of 149,000 births in six educational centers located in Tehran. The control group matched with the study group regarding birth date, maternal age, socioeconomic status and living environment. The outcomes for the control and study groups were studied and compared in the following areas: premature rupture of membrane, pregnancy length, fetal presentation, hydramnios, fetal death, sex ratio (male to female ratio) and other anomalies. Results: Anencephaly increased the likelihood of premature rupture of membrane by a factor of seven (p < 0.001). Pre-term birth was six times more likely (p < 0.005) and acephalic fetal presentation was 46% (p < 0.0005). In the study group, sex ratio was 0.52 and in control was 1.68 (p < 0.025). Further, hydramnios appeared in 90% of the study group. Finally, the general likelihood of any abnormality was 19 times (p < 0.0005) greater in the study group than the control group. Conclusions: Considering the clear correlation between anencephaly and pregnancy complications, precise prenatal care, early diagnosis and treatment are strongly indicated in order to avoid serious maternal complications.
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