PROJECT SUMMARY/ABSTRACT During early human pregnancy, placental extravillous trophoblasts invade and remodel the uterine spiral arteries into distensible low-resistance vessels to promote placental perfusion and thus fetal development. A defect in uterine spiral artery remodeling (SAR) is the primum movens step that underpins adverse human pregnancy, particularly preeclampsia, which leads to systemic vascular dysfunction in and increased morbidity and mortality of the mother and offspring. However, there are no experimental primate models of defective SAR, noninvasive methods to detect the defect in SAR in early pregnancy or therapeutic modalities to prevent the maternal and offspring vascular dysfunction. We established a model of impaired SAR by slightly elevating estradiol in the first trimester of baboon pregnancy. This model is characterized by a decrease in extravillous trophoblast vascular endothelial growth factor (VEGF) expression, increase in placental expression and maternal serum levels of the soluble fms-like tyrosine kinase-1 receptor (sFlt-1) that suppresses VEGF bioavailability, maternal (published) and offspring (preliminary) vascular dysfunction, reduced fetal growth and increased incidence of perinatal demise. We also employed B- flow/spatio-temporal image correlation (STIC) M-mode ultrasonography to detect SAR impairment in early pregnancy. Importantly, ultrasound- mediated/microbubble-facilitated gene delivery (UMGD) of VEGF to the placental basal plate of estradiol- treated baboons early in pregnancy abolished the defect in SAR. However, it has not been established whether reversing the defect in SAR by UMGD of VEGF will prevent maternal and offspring vascular dysfunction. The foundation built upon this primate model during the recent R01 HD 93070 project period, provides a highly unique opportunity to test the novel hypothesis that VEGF gene delivery to restore SAR will prevent vascular dysfunction in the mother, fetus and o