Preeclampsia, the leading cause of maternal mortality in developed nations, increases perinatal mortality five fold. The primary defect in the disorder is reduced placental perfusion. Recent data supports reduced placental perfusion translating to a multisystemic disease by actions to alter endothelial function. It is also evident that maternal constitutional factors such as prepregnancy obesity and insulin resistance interact with placental factors to increase the risk of preeclampsia. Many risk factors for preeclampsia (obesity, hypertension etc.) are similar to those for atherosclerosis, which also has vascular endothelium as a primary target. In addition to the role of endothelial dysfunction in the two disorders there are many other similarities including lipid alterations and evidence of oxidative stress. Hyperhomocysteinemia is a risk factor for atherosclerosis and recent data also indicate increased prevalence of hyperhomocysteinemia in preeclamptic women. Hyperhomocysteinemia can be caused by nutritional deficiency (folate, vitamin B6 and B12) as well as metabolic disorders such as renal disease. In addition, genetically determined deficits of homocysteine metabolism elevate plasma concentrations. We will determine the prevalence of hyperhomocysteinemia in nulliparous and recurrent preeclamptic patients and examine mechanisms by which homocysteine might be increased (nutritional, metabolic and genetic). We will also probe how homocysteine might facilitate the development of preeclampsia; examining lipid changes and markers of oxidative stress and endothelial dysfunction. The confirmation of hyperhomocysteinemia as a risk factor for preeclampsia is especially important since elevated homocysteine can be reduced by administration of folate, vitamin B6 or B12 in patients with dietary deficiency and in larger doses can at least partially overcome genetically determined enzyme deficiencies. Finally, we will probe whether there is a unique sensitivity to homocysteine during pregnancy. Preeclampsia is completely reversible with delivery despite persistence of elevated homocysteine concentrations, yet these hyperhomocysteinemic women will have increased risk for atherosclerosis in later life. We will examine mice with hyperhomocysteinemia induced acutely by diet and a transgenic mouse deficient in a homocysteine metabolizing enzyme to determine if pregnancy presents unique risk for vascular and metabolic dysfunction. These studies could provide insight into what appears to be a unique sensitivity to endothelial dysfunction during pregnancy and whether acute (during pregnancy) insults are as important as life long exposure.
