A Biopolymer‐Stabilized VEGF Chimera is Maternally Sequestered and Prevents Placental Ischemia Induced Increases in Blood Pressure in the Reduced Uterine Perfusion Pressure Model of Preeclampsia
Authors: LOGUE OMAR , Mahdi Fakhri , Chapman Heather , George Eric Matthew , Bidwell Gene Lee 
Published: November 2023

Preeclampsia (PE) is a form of gestational hypertension that complicates 3–5 % of pregnancies in the United States. The etiology of PE originates from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases factors that drive the pathophysiology. One of these pathological factors, soluble fms‐like tyrosine kinase‐1 (sFlt‐1), causes angiogenic imbalance by sequestering vascular endothelial growth factor (VEGF), leading to endothelial dysfunction and the manifestation of hypertension in the gravid female. Therapies targeted to factors, including sFlt‐1, that drive the maternal syndrome have the potential to revolutionize treatment of preeclampsia. However, such therapeutics must be developed with consideration for their potential adverse effects on fetal development. We have previously shown that elastin‐like polypeptide (ELP), a bioengineered protein polymer, does not cross the placenta and has the potential to prevent fetal exposure to attached therapeutics. With the goal of targeting sFlt‐1 while simultaneously preventing fetal exposure, we fused human VEGF121 to the ELP carrier (ELP‐VEGF). ELP‐VEGF was administered to timed‐pregnant Sprague‐Dawley rats that had undergone the reduced uterine perfusion pressure (RUPP) surgery. The RUPP surgery induces placental ischemia and evokes the major pathophysiological events observed in clinical cases of PE. In vitro studies demonstrated that serum from RUPP rats inhibited endothelial cell tube formation, but addition of ELP‐VEGF at a dose of 10 nM restored tube formation in the presence of RUPP serum. Chronic administration of ELP‐VEGF via intraperitoneal minipumps in pregnant rats lead to a linear, dose dependent increase in plasma ELP‐VEGF levels. The protein accumulated in maternal kidneys, aorta, liver, and placenta, but was undetectable at therapeutic doses in the pups. Chronic administration in the RUPP model at 5 mg/kg/day attenuated the hypertensive response seen in saline‐treated RUPPed maternal dams. Moreover, ELP‐VEGF at up to 5 mg/kg/day had no deleterious effect on fetal weight or placental efficiency. Dams treated with ELP‐VEGF had significantly increased urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. However, dams also experienced dose‐dependent adverse events likely related to the continuous intraperitoneal infusion method, including ascites production, neovascular tissue encapsulation around the minipump, and, at the 10 mg/kg/day dose, fetal loss. We report that ELP‐VEGF at 5 mg/kg/day offers the potential to ameliorate placental ischemia‐associated hypertension, but careful dosing and optimization of the delivery route are necessary to avoid adverse effects on mother and offspring.

Support or Funding Information

Supported by: AHA 13SDG16490006 to Bidwell, NIH 1R00HL116774 to George, NIH 1R01HL121527 to Bidwell, 5 T32 HL 105324‐5 to Logue, 2T32HL105324‐06 to Logue