Normal pregnancy is associated with reduction in systemic vascular resistance, increased renal blood flow and decreased arterial pressure. In 5 to 10 percent of pregnancies, women develop a condition called preeclampsia characterized-by proteinuria, increased systemic and renal vascular resistance and pregnancy-induced hypertension (PIH); however, the mechanisms underlying this disorder have not yet been clearly identified. Reduction in uteroplacental perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger the increases in systemic vascular resistance and PIH; however, the intermediary vascular and cellular mechanisms involved are unclear. The overall objective of this proposal is to test the central hypothesis that localized reduction in uteroplacental perfusion during late pregnancy is associated with generalized decrease in endothelium-dependent vascular relaxation and increase in vascular smooth muscle reactivity leading to generalized vasoconstriction, increased vascular resistance and hypertension. The decreased vascular relaxation occurs as a result of inhibition of the nitric oxide-cGMP and/or the prostacyclin-cAMP relaxation pathway. The increased vascular smooth muscle reactivity occurs as a result of increased sensitivity of vascular smooth muscle to vasoconstrictors leading to increased