From the UMR 8638 (L.T.-A., K.P., L.H., M.V., N.G.-E.), CNRS, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Sorbonne Paris Cité, Paris, France.
UMR 168 CNRS Institut Curie, PSL Research University, Institut Pierre Gilles de Gennes, Paris, France (L.A., S.Dumas, S. Descroix.).
Hypertension. 2019 Jul;74(1):145-153. doi: 10.1161/HYPERTENSIONAHA.118.12380. Epub 2019 May 13.
Preeclampsia is a hypertensive pregnancy disease associated with a massive increase in sFlt-1 (soluble form of the vascular endothelial growth factor 1) in the maternal circulation, responsible for angiogenic imbalance and endothelial dysfunction. Pilot studies suggest that extracorporeal apheresis may reduce circulating sFlt-1 and prolong pregnancy. Nonspecific apheresis systems have potential adverse effects because of the capture of many other molecules. Our concept is based on a specific and competitive apheresis approach using VEGF (vascular endothelial growth factor) functionalized magnetic beads to capture sFlt-1 while releasing endogenous PlGF (placental growth factor) to restore a physiological angiogenic balance. Magnetic beads were functionalized with VEGF to capture sFlt-1. Experiments were performed using PBS, conditioned media from human trophoblastic cells, and human plasma. The proof of concept was validated in dynamic conditions in a microfluidic device as an approach mimicking real apheresis. Magnetic beads were functionalized with VEGF and characterized to evaluate their surface ligand density and recognition capabilities. VEGF-coated magnetic beads proved to be an efficient support in capturing sFlt-1 and releasing PlGF. In static conditions, sFlt-1 concentration decreased by 33±13%, whereas PlGF concentration increased by 27±10%. In dynamic conditions, the performances were improved, with 40% reduction of sFlt-1 and up to 2-fold increase of free PlGF. The sFlt-1/PlGF ratio was reduced by 63% in the plasma of preeclamptic patients. Apheresis was also associated with VEGF release. A ligand-based approach using VEGF-coated beads is an effective approach to the capture of sFlt-1 and the release of endogenous PlGF. It offers new perspectives for the treatment of preeclampsia.
子痫前期是一种与母体循环中可溶性血管内皮生长因子 1 型（sFlt-1）大量增加相关的妊娠高血压疾病，导致血管生成失衡和内皮功能障碍。初步研究表明，体外血液净化可能会减少循环中的 sFlt-1 并延长妊娠时间。由于非特异性血液净化系统可能会捕获许多其他分子，因此存在潜在的不良反应。我们的概念基于使用 VEGF（血管内皮生长因子）功能化的磁性珠的特异性和竞争性血液净化方法，以捕获 sFlt-1，同时释放内源性 PlGF（胎盘生长因子）以恢复生理血管生成平衡。磁性珠通过 VEGF 功能化以捕获 sFlt-1。实验使用 PBS、人滋养细胞条件培养基和人血浆进行。在微流控装置中的动态条件下验证了概念验证，作为模拟真实血液净化的方法。将 VEGF 功能化的磁性珠进行功能化，以评估其表面配体密度和识别能力。VEGF 涂层的磁性珠被证明是捕获 sFlt-1 和释放 PlGF 的有效载体。在静态条件下，sFlt-1 浓度降低了 33±13%，而 PlGF 浓度增加了 27±10%。在动态条件下，性能得到了改善，sFlt-1 的减少了 40%，游离 PlGF 的增加了 2 倍。子痫前期患者血浆中的 sFlt-1/PlGF 比值降低了 63%。血液净化还与 VEGF 的释放有关。使用 VEGF 涂层珠的配体基方法是一种有效的捕获 sFlt-1 和释放内源性 PlGF 的方法。它为子痫前期的治疗提供了新的前景。
