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Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3 Ϫ/ϪKO , where KO is knockout) and wild-type (WT) mice (NOS3 ϩ/ϩWT ) were crossbred to produce homozygous NOS3 Ϫ/ϪKO , maternally derived heterozygous (NOS3 ϩ/Ϫmat , mother with NOS3 deficiency), paternally derived heterozygous (NOS3 ϩ/Ϫpat , normal mother), and NOS3 ϩ/ϩWT litters. Number of fetuses per litter was smaller in NOS3Ϫ/ϪKO and NOS3 ϩ/Ϫmat compared with NOS3 ϩ/Ϫpat and NOS3 ϩ/ϩWT mice. Adult female mice from these litters (7-8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3 Ϫ/ϪKO and NOS3 ϩ/Ϫpat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life.

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Relative uterine inactivity during pregnancy changes to vigorous rhythmic contractility during labour. We hypothesized that mechanisms involved in the regulation of uterine quiescence and contractility differ between term and preterm myometrium and in labour and non-labour states. Myometrial strips, prepared from biopsies taken at Caesarean section from labouring and non-labouring women preterm and at term, were mounted in organ chambers for isometric tension recording. Oxytocin (10(-9) mol/l) was added to maintain stable contractions, and effects of various inhibitors of uterine contractility were studied. The inhibitory effects of L-type Ca(2+)-channel blocker nifedipine and ATP-sensitive K(+)-channel opener pinacidil were greater in myometrium from the non-labour versus the labour group, both preterm and at term. In addition, pinacidil's effect was greater at term compared with preterm in the non-labour group. Mg(2+) and the nitric oxide donor sodium nitroprusside significantly inhibited contractility in all groups without significant differences with regard to labour or gestational age. Decreased inhibition of human uterine contractility by L-type Ca(2+)-channel blockers and K(+)(ATP)-channel openers in preterm and term labour may reflect changes in expression and activity of these channels. Effects of nitric oxide and Mg(2+) are not affected by gestational age or labour.