Selective upregulation of VEGF receptor 2 normalizes maternal and fetal outcomes in a rat model of preeclampsia

Preeclampsia is the leading cause of maternal and fetal morbidity and mortality in the United States. Maternal hypertension occurs to increase blood perfusion but it is inadequate, resulting in growth-restriction. Improving placental perfusion could alleviate maternal hypertension and improve fetal outcomes. An imbalance between vasodilators and vasoconstrictors mediates the pathophysiology of preeclampsia shifting the balance toward vasodilation would be beneficial for maternal and fetal outcomes. Our hypothesis is that increasing the VEGFR2 receptors in the uterine tissue will improve the pathophysiology of preeclampsia. To test our hypothesis, we used the reduced uterine perfusion pressure rat model (RUPP) and treatment with non-viral l-tyrosine polyphosphate (LTP) nanoparticles containing the plasmid DNA for VEGFR2. The LTP nanoparticles are administered in one dose at <i>gestational day 14</i> (same day as surgery). Maternal blood pressure, measured at <i>gestational day 21</i> in anesthetized rats, mean arterial pressure was decreased in the RUPP rats treated with LTP-VEGFR2 nanoparticles (72.8 ± 3.6 mmHg) compared with control RUPP (100 ± 6 mmHg, <i>P</i> = 0.01). In addition, myogenic reactivity of uterine arteries isolated from RUPP treated with LTP-VEGFR2 demonstrated decreased myogenic reactivity compared with RUPP. At the 120 mmHg pressure step, arteries from RUPP treated with LTP-VEGFR2 nanoparticles increased in diameter by 42 ± 12% compared with a decrease of 22 ± 5% in untreated RUPP (<i>P</i> = 0.003). The role for the VEGF myogenic studies was confirmed with VEGF neutralizing antibodies. In addition, treatment with LTP-VEGFR2 nanoparticle treatments increased fetal and placental weights in RUPP rats. This study demonstrates that overexpression of VEGFR2 by LTP nanoparticles may provide a novel therapeutic agent for the treatment of preeclampsia.<b>NEW & NOTEWORTHY</b> This study demonstrates that overexpression of VEGFR2 by LTP nanoparticles may provide a novel therapeutic agent in the treatment of preeclampsia, which would improve maternal and fetal outcomes. The VEGFR2 nanoparticles successfully decreased MAP, while also normalizing the myogenic response of uterine arteries and improving fetal and placental weights.