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Validation of LTP nanoparticles as a gene delivery system: Maternal and Fetal Outcomes Unchanged by Delivery of Nonsense Plasmid VEGFR2 Nanoparticles
Author(s) -
Novak Jacqueline,
Balser Brittany Ann,
Yun Yang H,
Ramirez Rolando JJ
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.851.7
Subject(s) - fetus , perfusion , medicine , angiogenesis , endocrinology , preeclampsia , biology , pregnancy , genetics
Placental under‐perfusion is a hallmark of preeclampsia. Alterations in the maternal circulation have been well documented in preeclamptic mothers, however treatment options remain limited. An imbalance in angiogenic factors (via the VEGF pathway) favoring a vasoconstrictory phenotype and inadequate vascular remodeling contribute to the maternal hypertension. Delivery of LTP VEGFR2 nanoparticles shows normalization in mean arterial pressure, uterine vessel myogenic reactivity, and fetal growth restriction. We previously demonstrated that LTP nanoparticles seeded with plasmid for VEGFR2 improved MAP and vascular reactivity. The goals of these studies were to validate the maternal and fetal safety of our nanoparticle delivery system. The reduced uterine perfusion pressure rat model (RUPP) is used to investigate preeclampsia pathology with nonsense plasmid for VEGFR2 nanoparticles. In the RUPP Sprague‐Dawley dams, silver clips are placed on the abdominal aorta (0.2mm ID) and the utero‐ovarian arteries (0.1mm ID) on pregnancy day 14. SHAM rats undergo surgery without clip placement. On the same day as RUPP surgery, LTP nanoparticles with nonsense plasmid for VEGFR2 are injected into the uterine wall. On day 21 of gestation an anesthetized blood pressure is measured via carotid catheter then resistance‐sized uterine arteries (< 300μm) are harvested for study in an isobaric arteriograph. Resistance‐sized uterine arteries from nonsense VEGFR2 LTP nanoparticle treated RUPP rats displayed increased myogenic response to intraluminal pressure increases. Animals treated with nonsense plasmid for VEGFR2 were also hypertensive, similar to untreated RUPP (100.4±5.8 Hg). Finally, RUPP rats injected with non‐sense VEGR2 LTP nanoparticles displayed growth restriction comparable to untreated RUPP rats. . In conclusion, uterine injection of LTP nanoparticles with nonsense plasmid for VEGFR2 did not significantly alter resistance‐sized uterine artery myogenic responsiveness, maternal blood pressure or fetal weights in RUPP animals, thus pathology of RUPP remained intact. SHAM animals showed no changes to uterine artery myogenic reactivity, MAP and fetal outcomes. These data suggest LTP nanoparticles themselves did not detrimentally alter pregnancy outcomes. Additionally these results increase support for the efficacy of LTP nanoparticles as a novel gene therapy device to treat preeclampsia.