A Maternally Sequestered, Biopolymer-Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia.
A Maternally Sequestered, Biopolymer-Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia.
复制标题
一种母体隔离的生物聚合物稳定的血管内皮生长因子（VEGF）嵌合体，用于治疗先兆子痫。
DOI：
10.1161/jaha.117.007216
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发表时间：
2017-12-08
影响因子：
5.4
通讯作者：
Bidwell GL 3rd
中科院分区：
文献类型：
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作者：
Logue OC;Mahdi F;Chapman H;George EM;Bidwell GL 3rd
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). 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. ELP‐VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.
