The impact of reductions in uterine perfusion pressure on uterine arterial reactivity in gravid rats and L-tyrosine polyphosphate nanoparticles as a potential in vivo gene delivery device.

摘要

Reductions in uterine perfusion pressure are thought to be a central component of the pathological pregnancy disease, preeclampsia. Preeclampsia is a hypertensive disorder of pregnancy characterized by vascular dysfunction and end organ underperfusion and is the leading cause of maternal and fetal morbidity and mortality in the United States and throughout the world. Uterine arterial reactivity and structural mechanics during preeclampsia are poorly understood and likely contributed to the pathophysiology of the maternal hypertension and altered fetal growth demonstrated in this disease. The first aim of this dissertation project was to characterize the impact of reductions in uterine perfusion pressure on maternal and fetal pregnancy outcomes. Maternal hypertension and fetal morphometrics have been examined in response to reductions in uterine perfusion pressure. The second aim of this research was to characterize the vascular behavior and structural biophysical mechanics of resistance-caliber uterine arteries in response to reductions in uterine perfusion pressure. Vascular behavior was examined using a pressurized arteriograph where myogenic reactivity, agonist induced vasodilation and vasoconstriction, and passive structural mechanics were assessed. The third aim of this research involved testing the efficacy of a novel L-tyrosine based gene delivery device. L-tyrosine polyphosphate (LTP) nanoparticles have demonstrated promise as a potential intracellular gene delivery device aimed at therapeutic avenues however; the in vivo efficacy of the delivery vehicle has been unknown. We aimed to prove the concept that LTP nanoparticles encapsulated with plasmid DNA would be efficacious as an in vivo gene delivery device in the rat uterus.;Chronic reductions in uterine perfusion pressure resulted in maternal hypertension and severe fetal growth restriction in pregnant rats suggesting an integral role of uterine perfusion pressure on maternal and fetal responses to the pathology. Uterine artery reactivity was found to be altered towards a constrictive phenotype in response to chronic reductions in uterine perfusion pressure with increased myogenic reactivity and decreased agonist induced vasodilation. Structural parameters of resistance-caliber uterine arteries were unaltered in response to the pathology while biophysical mechanical properties of the uterine arteries were altered. Distensibility was altered in isolated resistance-caliber uterine arteries isolated from reductions in uterine perfusion pressure gravid rats suggesting a potential contributing factor to the vascular dysfunction described above. Nanoparticles formulated from L-tyrosine polyphosphate successfully delivered plasmid DNA in vivo to the rat uterine tissue. These data suggest that uterine arterial reactivity is altered in response to reductions in uterine perfusion pressure and that LTP nanoparticles encapsulated with plasmid DNA may have potential as a delivery platform for therapies aimed at diseases of the uterus and uterine vasculature.