Enhanced growth and improved vascular function in offspring from successive pregnancies in endothelial nitric oxide synthase knockout mice

Objective Transgenic mice that lack endothelial nitric oxide synthase have offspring with growth deficiency and abnormal vascular reactivity in later life. Our objective was to evaluate the role of parity in the modulation of the fetal programming of growth and vascular responses in these transgenic mice. Study design Oligoparous (0-2 previous pregnancies) and multiparous (5-9 previous pregnancies) nitric oxide synthase knockout (−/−KO) female mice were bred with nitric oxide synthase−/−KO and wild type (+/+WT) male mice to produce nitric oxide synthase−/−KO and maternally derived heterozygous (+/−Mat) litters. The pups were weighed weekly. Carotid arteries of the adult females from these litters were used for in vitro vascular reactivity studies. Results Nitric oxide synthase knockout and nitric oxide synthase maternal litters that were born to oligoparous mothers had significant growth lag compared with corresponding multiparous litters. Length-tension characteristics were not different between the groups. However, optimal diameter, which is a measure of vascular tensile properties and resistance, was decreased in oligoparous compared with multiparous female offspring. Acetylcholine-mediated vasorelaxation was abolished, and contraction by phenylephrine and Ca++ was increased in oligoparous, but not multiparous, female offspring (P< .05). Conclusion These data support the role of abnormal uterine environment in the fetal programming of postnatal growth and vascular function in later life. Successive pregnancies may lead to maternal uterine adaptations that bypass the lack of a functional nitric oxide synthase, which leads to improvement in postnatal growth and vascular function in the offspring. Given the reported effect of parity on the risk of preeclampsia, similar mechanisms may be operative in human pregnancy.