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.
Hypercholesterolemia Promotes a CD36-dependent and Endothelial Nitric-oxide Synthase-mediated Vascular Dysfunction
