VEGF (Vascular Endothelial Growth Factor) Functionalized Magnetic Beads in a Microfluidic Device to Improve the Angiogenic Balance in Preeclampsia

Abstract

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. VEGFcoated 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 ligandbased 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.

Upregulation of VEGF and PEDF in Placentas of Women with Lower Extremity Venous Insufficiency during Pregnancy and Its Implication in Villous Calcification

“…The increase in HIF in a hypoxic condition is associated with VEGF activity [23, 24]. The increase in the activity and expression of VEGF in situations of high blood pressure, such as preeclampsia, is well known [25]. Zhang et al [26] showed how increased VEGF activity in placentas in preeclampsia produced an increase in apoptosis.…”

Ghrelin promotes angiogenesis by activating the Jagged1/Notch2/VEGF pathway in preeclampsia

“…Vascular endothelial growth factor (VEGF), a biomarker of angiogenesis, is necessary for promoting placental vascularization. It has been suggested that a decrease in VEGF in pregnant women may affect the recasting of the uterine spiral artery, potentially leading to PE 10 …”

“…It has been suggested that a decrease in VEGF in pregnant women may affect the recasting of the uterine spiral artery, potentially leading to PE. 10 wGhrelin, a 28 amino-acid hormone produced primarily by the stomach, was initially shown to strongly stimulate growth hormone release, promote food intake and regulate energy homeostasis by binding to its specific receptor, GHSR1a. Ghrelin has been shown to stimulate endothelial cells angiogenesis through extracellular regulated protein kinases (ERK) signaling pathway 11 and has been found to be in the regulation of blood pressure.…”

Abnormal expression and clinical significance of 25-hydroxyvitamin D and sFlt-1 in patients with preeclampsia

“…9 Indeed, competitive binding of sFlt-1 with VEGF has been shown to abolish the biological functions of VEGF and PLGF, leading to endothelial dysfunction. 10 In patients with preeclampsia, the ratio of sFlt1 to PLGF may be useful as a biomarker to predict preeclampsia. For instance, urinary sFlt-1/PLGF ratio is reported to be effective in differentiating women with severe preeclampsia from healthy pregnant women, 11 and patients with preeclampsia have been shown to have increased serum levels of sFlt-1, and decreased circulating PLGF.…”