Perinatal development of endothelial nitric oxide synthase-deficient mice

The purpose of this study was to evaluate the influence of endothelial nitr ic oxide synthase (eNOS) deficiency on fetal growth, perinatal survival, an d limb development in a mouse model with a targeted mutagenesis of the Nos3 gene. Wild-type (Nos3(+/+)) and eNOS-deficient fetuses (Nos3(-/-)) were ev aluated on Gestational Day (E)15 and E17, and newborn pups were observed on Day 1 of life (D1). The average term duration of pregnancy was 19 days. Fo r the evaluation of postnatal development, a breeding scheme consisting of Nos3(+/-) x Nos3(+/-) and Nos3(-/-) Nos3(-/-) mice was established, and off spring were observed for 3 wk. Southern blotting was used for genotyping. N o significant differences in fetal weight, crown-rump lengths (CRL), and pl acental weight were seen between Nos3(+/+) and Nos3(-/-) fetuses on E15. By E17, Nos3(-/-) fetuses showed significantly reduced fetal weights, CRL, an d placental weights. This difference in body weight was also seen throughou t the whole postnatal period. In pregnancies of Nos3(-/-) females, the aver age number of pups alive on D1 was significantly decreased compared to eith er E15 or E17. Placental histology revealed no abnormalities. On E15, E17, and D1, Nos3(-/-) fetuses demonstrated focal acute hemorrhages in the dista l limbs in 0%, 2.6%, and 5.7%, respectively, of all mutant mice studied on the respective days. Bone measurements showed significantly shorter bones i n the peripheral digits of hindpaws of Nos3(-/-) newborns. We conclude mice deficient for eNOS show characteristically abnormal prenatal and postnatal development including fetal growth restriction, reduced survival, and an i ncreased rate of limb abnormalities. The development of this characteristic phenotype of eNOS-deficient mice dates back to the prenatal development du ring the late third trimester of pregnancy.