Cardiovascular disease is the major cause of morbidity and mortality in most societies. Atherosclerosis is a major contributor to cardiovascular disease and, in many instances, is caused by hypercholesterolemia. The fetal environment is becoming a recognized risk factor for the development of hypercholesterolemia. We have demonstrated in an ApoE knockout mouse model that maternal hypercholesterolemia is a strong contributor to hypercholesterolemia and atherosclerotic changes in the offspring when they become adults. Our preliminary studies, in addition, have shown pathologic changes in the liver and kidney as well as molecular markers in the affected animals that are consistent with fetal/neonatal programming of cholesterol metabolism. It is unknown whether these changes are primarily determined in utero or during early postnatal period. Our general hypothesis is that that fetal programming is a major contributor to the overall risk to develop cardiovascular disease in adulthood. We believe that he predisposition to develop hypercholesterolemia and atherosclerosis is primarily determined during in utero development. Our long term goal is to understand the detailed mechanisms underlying fetal/neonatal programming of atherosclerosis, and to use this knowledge to devise preventive and therapeutic strategies aimed at reducing the burden of atherosclerosis and cardiovascular disease.
The specific aims of this study include 1) Cross-fostering studies to determine whether the predisposition to atherosclerotic disease is determined in utero or postnatally and 2) To determine vascular function and blood pressure patterns in the adult offspring of cross-bred mice. To achieve the specified goals we will remove the natural litters of cross-bred offspring of ApoE deficient mice with wild type mice and cross-foster them. We will determine cholesterol levels, in vivo blood pressure and in vitro vascular reactivity in these offspring at eight months of age. Similar studies will be done with offspring that remain with their natural mothers during the fostering period. This study aims to achieve a better understanding of the mechanisms of fetal/neonatal programming of atherosclerosis. Specifically, we will determine the overall contribution of the maternal environment before versus after birth to this phenomenon. In addition, we will study the effects of fetal programming on blood pressure and vascular reactivity in adulthood.
| Goharkhay, Nima; Tamayo, Esther H; Yin, Huaizhi et al. (2008) Maternal hypercholesterolemia leads to activation of endogenous cholesterol synthesis in the offspring. Am J Obstet Gynecol 199:273.e1-6 |
