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Fetal Physiological Programming

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

Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas

Submitted 1 June 2004 ; accepted in final form 25 December 2004

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.

fetal origin of adult disease; pregnant mice; uterine environment; vascular reactivity in vitro

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