Abstract-Antagonism of vascular endothelial growth factor (VEGF) signaling by soluble fms-like tyrosine kinase 1 occurs during preeclampsia and is proposed to play an important role in the pathogenesis of preeclampsia. We reported recently that hypertension associated with chronic reductions in uteroplacental perfusion pressure (RUPP) is associated with increased soluble fms-like tyrosine kinase 1 and decreased free VEGF. Key Words: preeclampsia Ⅲ gestation Ⅲ VEGF Ⅲ blood pressure Ⅲ angiogenic P reeclampsia is a major obstetric problem that affects Ϸ5% of all pregnancies and is a significant source of maternal and neonatal morbidity and mortality. 1 Moreover, the incidence of preeclampsia has seen a 40% increase in recent years. 2 Although the preeclamptic syndrome has been well characterized, and many studies indicate that hypertension, proteinuria, endothelial cell dysfunction, and insufficient placentation are key features of this disorder, 3,4 the underlying pathophysiological mechanisms of this disorder remain unclear.Recent studies have established the existence of an imbalance between proangiogenic and antiangiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor, and soluble fms-like tyrosine kinase 1 (sFlt-1) in preeclamptic women. 5-10 Moreover, findings from several clinical studies suggest that alterations in circulating sFlt-1 concentrations may presage the clinical onset of preeclamptic symptoms. 5,[11][12][13] Viewed in concert with recent experimental studies in animals, it appears that this dysregulation of angiogenic factors may play a key role in the pathogenesis of preeclampsia. 9,10,14 -19 Although the mechanisms underlying the overexpression of antiangiogenic factors, such as sFlt-1, are currently unresolved, in vitro and in vivo evidence suggest that placental hypoxia/ischemia may initiate this imbalance of angiogenic factors. 14,16,20 Both Gilbert et al 14 and Makris et al 16 have shown in vivo that chronic placental ischemia results in elevated circulating levels of sFlt-1 and hypertension. In addition, previous studies have shown that reduced uterine perfusion pressure (RUPP) is associated with decreased

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Recent evidence indicates formerly preeclamptic women have endothelial dysfunction and increased risk for cardiovascular and renal disease in later life. Despite these observations it remains unclear if these sequelae are due to persistent effects of placental ischemia or are related to underlying genetic or environmental factors associated with preeclampsia. To this end, we employed our model of hypertension associated with reduced uterine perfusion pressure (RUPP) to determine if placental ischemia is associated with persistent changes in vascular function independent of other risk factors. We hypothesized that formerly hypertensive rats with placental ischemia during pregnancy would have endothelial dysfunction four months post‐partum (RUPP‐PP) when compared to normal pregnant post‐partum dams (NP‐PP). Arterial pressure (115 ± 6 vs. 113 ± 5 mmHg) and body weight (272 ± 7 vs. 270 ± 5 g) were not different between NP‐PP and RUPP‐PP groups. Wire myography revealed that endothelial dependent relaxation to ACh was impaired in the RUPP‐PP vs. NP‐PP as evidenced by a rightward shift in the concentration response curve (‐log EC50 ‐6.0 ± 0.3 vs. ‐6.8 ± 0.2; P<0.05). Smooth muscle dependent relaxation to sodium nitroprusside was unchanged between groups. The present data indicate that vascular endothelial dysfunction is a persistent effect of placental ischemia independent of other cardiovascular risk factors.