Novel Methods: Intrauterine Assessment of Fetal Growth and Development with High Resolution Ultrasound in a Mouse Model

Principal Investigator: Kathleen Vincent, MD

three different strains of mice used in experiments - Linda Bartlett (photographer)Although several observational studies have implicated uterine environment and genetic imprinting in the etiology of several disease processes, there is a lack of direct studies. Nitric oxide generated by NOS3 (endothelial NOS, eNOS) in the vasculature is believed to be one of the most important factors in modulating vascular tone. NO's role in regulating blood pressure is even more evident during pregnancy, a physiological state that requires plasma volume expansion and a decrease in vascular resistance in order to maintain adequate placental perfusion for fetal growth and development. Disturbances in the cardiovascular adaptations to pregnancy are believed to be responsible for some of the most common obstetrical complications, such as fetal growth restriction and preeclampsia. In humans, an association between polymorphisms in some of the genes controlling cardiovascular function and adverse pregnancy outcomes, including fetal growth restriction, have been described (Savvidou et al., 2001; Hefler et al., 2002; Zhang et al., 2003).

The relationship between the inheritance of these polymorphisms and the adverse outcome has not been extensively studied in humans. Transgenic mice offer an opportunity for the study of the genetic and uterine environment effects on fetal programming. Programming has permanent consequences that alter organ responses in later life and can modify susceptibility to disease. These effects differ between females and males. Studies in eNOS deficient mice show abnormal postnatal development and abnormal vascular function in later life depending on the parental source of the abnormal gene.

These mice represent a unique model to evaluate the role of the genetic background and uterine environment in fetal development especially the cardiovascular system. Studying the offspring of those mice provide a way to determine if the fetal programming is transmitted through generations. We have shown that lack of NOS3 expression is associated with abnormal fetal growth and vascular responses in mice. In preliminary investigations, we also found that the phenotype of the pups and adult offspring depends on the number and parental source of the allelic mutations. In the proposed study, we will measure parameters associated with placental perfusion, fetal size, and cardiac function in utero during fetal development with high resolution ultrasound. These findings will be correlated with postnatal parameters of weight and vascular response.