In utero programming of vascular function in transgenic mice lacking endothelial nitric oxide synthase

The fetal origin of adult disease or 'Barker Hypothesis' states that susceptibility to diseases in adult life is programmed during prenatal life. In order for the fetus to survive under adverse situations, adaptations known as programming take place. Those changes may have permanent effects on organ systems, as the cardiovascular and metabolic systems. A strong association has been found between low birth weight and death from cardiovascular disease in adult life. However the observed association between an unfavorable uterine environment and diseases may be confounded by a genetic predisposition for the particular disease. For this purpose, we used a transgenic mouse lacking the endothelial nitric oxide synthase or NOS3. NOS3 produce nitric oxide which regulate blood pressure during pregnancy. To determine the role of uterine environments versus parental genetic contribution, we use heterozygous mice having similar genetic makeup but developing in different uterine environments. In offspring NOS3 heterozygous and homozygous changes in vascular function, vascular gene expression, and renal morphology were examined. Our results show that the vascular phenotype in heterozygous inheriting the functional NOS3 from the father and developing in NOS3-/-KO mothers (NOS3+/-Mat) is similar to NOS3-/-KO mice offspring. In contrast, the vascular phenotype in heterozygous mice in which the mutant NOS3 gene is from the father and develop in NOS3 +/+WT mothers (NO3+/-Pat) is similar to NOS3 +/+WT mice. Those responses were also obtained in the NOS3 +/-Mat and NOS3+/-Pat heterozygous male, confirming our previous findings and that fetal vascular programming is not gender-specific. Fetal vascular programming, also effect the expression of genes involved in vascular development and fetal renal morphology. Using embryo-transfer procedure we demonstrate that fetal vascular programming of abnormal vascular function in later life depends on an abnormal uterine environment rather than genetic imprinting. In addition, we also found that successive pregnancy may lead to maternal uterine adaptations that permit to the fetus to have a normal vascular development. Hence, this animal model is well-suited to investigate the relative contributions of the uterine environment versus parental genetic factors in determining fetal vascular programming and vascular function in adult life.