Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase

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(-/-KO), where KO is knockout) and wild-type (WT) mice (NOS3(+/+WT)) were crossbred to produce homozygous NOS3(-/-KO), maternally derived heterozygous (NOS3(+/-mat), mother with NOS3 deficiency), paternally derived heterozygous ( NOS3(+/-pat), normal mother), and NOS3(+/+WT) litters. Number of fetuses per litter was smaller in NOS3(-/-KO) and NOS3(+/-mat) compared with NOS3(+/-pat) and NOS3(+/+WT) 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(-/-KO) and NOS3(+/-mat) compared with NOS3(+/-pat) and NOS3(+/+WT) mice. Acetylcholine caused vasorelaxation in NOS3(+/-pat) and NOS3(+/+WT) and contraction in NOS3(-/-KO) and NOS3(+/-mat) mice. Responses to phenylephrine and Ca2+ were increased in NOS3(-/-KO) and NOS3(+/-mat) compared with NOS3(+/-pat) and NOS3(+/+WT) mice. Relaxation to isoproterenol was decreased in NOS3(-/-KO) and NOS3(+/-mat) vs. NOS3(+/-pat) and NOS3(+/+WT) mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS+/-mat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3(+/-pat) 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.