A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

BACKGROUND Preeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms-like tyrosine kinase-1, is believed to sequester vascular endothelial growth factor (VEGF), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms-like tyrosine kinase-1 while simultaneously preventing fetal exposure to VEGF, we fused VEGF to elastin-like polypeptide, a biopolymer carrier that does not cross the placental barrier (ELP-VEGF). METHODS AND RESULTS ELP-VEGF restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long-term administered ELP-VEGF in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long-term administration of ELP-VEGF in a placental ischemia rat model achieved dose-dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day. ELP-VEGF infusion increased total plasma soluble fms-like tyrosine kinase-1 levels but dramatically reduced free plasma soluble fms-like tyrosine kinase-1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. ELP-VEGF at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose-dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump. CONCLUSIONS ELP-VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.