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

Monica Longo, Venu Jain, Yuri P. Vedernikov, Radek Bukowski, Robert E. Garfield, Gary D. Hankins, Garland D. Anderson, George R. Saade

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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 knock-out) 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.

Original languageEnglish (US)
Pages (from-to)R1114-R1121
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume288
Issue number5 57-5
DOIs
StatePublished - May 1 2005

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Keywords

  • Fetal origin of adult disease
  • Pregnant mice
  • Uterine environment
  • Vascular reactivity in vitro

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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