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.
Longo
Monica
M
Dept. of Obstetrics and Gynecology, Division of Reproductive Sciences, Univ. of Texas Medical Branch, 301 Univ. Blvd., Rt. J-62, Galveston, TX 77555-1062, USA. molongo@utmb.edu
Jain
Venu
V
Vedernikov
Yuri P
YP
Bukowski
Radek
R
Garfield
Robert E
RE
Hankins
Gary D
GD
Anderson
Garland D
GD
Saade
George R
GR
D000109:Acetylcholine / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D005260:Female; D047109:Fetal Development / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D007545:Isoproterenol / Q000494:pharmacology; D008098:Litter Size; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010656:Phenylephrine / Q000494:pharmacology; D014599:Uterus / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D010656:Phenylephrine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D007545:Isoproterenol; D000109:Acetylcholine; D002118:Calcium