Preeclampsia increases perinatal mortality 5 fold, yet certain infants manifest no evident morbidity (e.g. only 30 percent growth restricted). Preeclampsia does not cause later cardiovascular disease, but they are associated. Women pregnant without preeclampsia have a lower incidence of later cardiovascular morbidity than the general population. This is not surprising. Risk factors (e.g. obesity) for this morbidity are also risks for preeclampsia. We propose that the heterogeneity of preeclampsia is due to interaction of reduced placental perfusion and maternal constitutional factors. We extend our studies of abnormal trophoblastic invasion in preeclampsia and endothelial dysfunction as a pathophysiological feature. Project 0004 characterizes bioactive materials produced uniquely or in excess by placental tissues maintained hypoxic in vitro and by placental tissue from preeclamptic women. This correlates closely with Project 0005 which tests the role of TNFalpha, produced by hypoxic placenta and increased in blood of preeclamptic women. Other materials identified by Project 0004 will be similarly tested. Project 0003, 0006 and 0002 test if these materials to alter endothelial and vascular function. The common risk factors for preeclampsia and cardiovascular morbidity suggest the pathogenesis of preeclampsia and endothelial dysfunction of atherosclerosis share common features. Project 0003 tests the hypothesis that oxidative stress, an excess of pro-oxidants over antioxidants, is involved in the pathophysiology of preeclampsia. Placental products, TNFalpha and iron metabolism will be examined as potential pro-oxidants. A detailed analysis of maternal lipid metabolism and insulin resistance is tested in Project 0007. Project 0002 tests the role of products of reduced placental perfusion (cytokines) and increased free fatty acids to alter prostanoid production. Project 0007 uses animal models to determine if the proposed changes in placental products, and/or oxidative stress change vascular responses relevant to preeclampsia. In Project 0008, the heterogeneity of preeclampsia is examined in the neonate. Detailed neurological and metabolic assessment test if the infant of the preeclamptic woman is different than an age-weight matched control. The data generated in the several studies will be accumulated in the Clinical Data Core/Project9001 where it will be used to test the feasibility of a clinical prediction. Additionally, fetal outcome and indicators of fetal/placental or maternal constitutional factors will be correlated to test if the heterogeneous fetal outcome may be determined by whether the major contribution to the pathophysiology is primarily fetal/placental or primarily .