description): Preeclampsia is the leading cause of maternal mortality in developed nations and increases perinatal mortality five fold. Many risk factors for preeclampsia (obesity, hypertension, insulin resistance, etc.) are similar to those for atherosclerosis. Another risk factor for atherosclerosis, homocysteine, has also been found to be increased in the blood of women with preeclampsia. The mechanism(s) by which homocysteine increases the risk of vascular disease and preeclampsia is largely unknown. Recent studies have demonstrated a strong association between increased plasma homocysteine and insulin resistance. This inter-relatedness of homocysteine and preeclampsia, atherosclerosis and insulin resistance prompted a search for a common mechanism that may be at work in each of these diseases. Insulin resistance affects lipid metabolism and beta-oxidation in critical ways that promote an atherogenic lipid profile, is associated with decreased endothelium-dependent vasorelaxation, and increases the risk of coronary and peripheral vascular disease. These same effects have been described in preeclampsia and likely contribute to the pathology of the disease. Furthermore, genetic studies indicate that disruption of beta-oxidation significantly increases the risk of preeclampsia. Therefore, we speculate that decreased beta-oxidation may be a common mechanism among these diseases, and homocysteine's effect on beta-oxidation will play a major role in the pathology of preeclampsia. We hypothesize that: 1) Hyperhomocysteinemia predisposes toward decreased beta-oxidation, and this effect will be exacerbated in pregnancy and 2) Decreased beta-oxidation during pregnancy will predispose women toward vascular complications associated with preeclampsia. The investigators will test these hypotheses by testing preeclamptic patients for markers of decreased beta-oxidation and relate this to patient's homocysteine concentration. They will investigate if hyperhomocysteinemia in a mouse model will affect beta-oxidation in both pregnant and nonpregnant animals. Lastly, the investigators will investigate the effect of pharmacologically induced decreased beta-oxidation on vasculature function in a nonpregnant and pregnant mouse model. These studies may lead to a greater understanding of the mechanism(s) by which hyperhomocysteinemia increases the risk of preeclampsia and to a more general understanding of the pathophysiology of preeclampsia suggesting novel therapeutic strategies.
| Powers, Robert W; Gandley, Robin E; Lykins, David L et al. (2004) Moderate hyperhomocysteinemia decreases endothelial-dependent vasorelaxation in pregnant but not nonpregnant mice. Hypertension 44:327-33 |
