A Biopolymer‐Fused Form of VEGF‐B for Treatment of Preeclampsia

Abstract

Preeclampsia is a complex syndrome hallmarked by the development of elevated blood pressure and proteinuria during the second and third trimester of pregnancy. There is an increase in a number of anti‐angiogenic factors in these women. These factors are believed to drive endothelial dysfunction and contribute to the elevation in blood pressure and other maternal symptoms. Vascular Endothelial Growth Factor (VEGF) is a family of growth factors that play a role in angiogenesis, endothelial cell health and maintenance. The VEGF family of proteins have varying affinities for the two major VEGF receptors, Flt‐1 and Flk‐1. Flk‐1 signaling is the major driver of VEGF‐induced angiogenesis and increased vascular permeability, whereas Flt‐1 is less angiogenic and may serve to modulate bioavailable VEGF. Furthermore, the soluble extracellular domain of Flt‐1 (sFlt‐1) is increased in early‐onset preeclampsia and serves as a VEGF trap. Previous studies have shown that administration of the isoform VEGF‐A in the Reduced Uterine Perfusion Pressure (RUPP) rat model significantly reduced blood pressure. While effective at reducing placental‐ischemia induced hypertension, VEGF‐A at high doses can produce unwanted side effects including unopposed angiogenesis and increased vascular permeability. These undesired effects of VEGF‐A are believed to be mediated by the Flk‐1 receptor. VEGF‐B, another isoform of VEGF, has a high affinity for Flt‐1 and s‐Flt1, but does not bind Flk‐1. We hypothesize that VEGF‐B will liberate endogenous VEGF‐A by successfully antagonizing circulating sFlt‐1, without inducing unwanted angiogenesis and increased vascular permeability. The purpose of this study was to determine the in‐vitro activity, pharmacokinetics, and biodistribution of a biopolymer delivered form of VEGF‐B compared to our previously published biopolymer‐delivered VEGF‐A. Both VEGF‐B and VEGF‐A were conjugated to an elastin like polypeptide (ELP) in order to aid in purification and delivery of the proteins. Angiogenic potential of ELP‐VEGF‐B and ELP‐VEGF‐A was evaluated using a tube formation assay in human umbilical vein endothelial cells (HUVECs). Pharmacokinetics, biodistribution, and placental transfer of fluorophore‐labeled ELP‐VEGF‐B were determined after intravenous (IV) or subcutaneous (SC) administration into pregnant rats. Tubule formation analysis indicated that ELP‐VEGF‐B had less angiogenic potential than ELP‐VEGF‐A. IV administration of ELPVEGF‐B cleared from the plasma in a bi‐phasic manner indicative of a two‐compartment pharmacokinetic model. Whereas, SC administration of ELP‐VEGF‐B showed accumulation of protein in the plasma over the first 24h, followed by a slow clearance. ELP‐VEGF‐B accumulated predominantly in the maternal liver, with lower but significant accumulation in the kidneys, placenta, and brain. Importantly, the biopolymer‐fused ELP‐VEGF‐B did not cross the placental barrier into the fetal circulation. In conclusion, our data suggest that ELP‐VEGF‐B has a similar pharmacokinetic profile to that of VEGF‐A, but does not induce as robust of an angiogenic response and may prove to be a safer therapeutic agent.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.