title: Effect of age and gender on the progression of adult vascular dysfunction in a mouse model of fetal programming lacking endothelial nitric oxide synthase.
abstract: The objective of this study was to investigate vascular function at different ages in a transgenic murine model of fetal vascular programming using a model of uteroplacental insufficiency induced by lack of endothelial nitric oxide synthase. Homozygous NOS3 knockout (KO) and wild-type (WT) mice were cross bred to produce WT, KO, and heterozygous that developed in WT (KOP) or KO (KOM) mothers. Male/female offspring from the four groups were killed at 7, 14, and 21 wk of age (n = 5-10/group), and carotid arteries were used for in vitro vascular studies. Responses to phenylephrine (PE), with/without N(G)-nitro-L-arginine methyl ester (L-NAME), angiotensin (ANG), acetylcholine (ACh), sodium nitroprusside, and isoproterenol (ISO) were studied. At 7 wk, only KO offspring showed higher contractile response to PE, whereas, at 14 and 21 wk, both KO and KOM had a higher response. Incubation with L-NAME abolished these differences. ANG contraction was higher in male KO in all age groups and in 21-wk-old females. Relaxation to ACh and ISO was absent in KO, and significantly decreased in KOM offspring in all age groups compared with KOP and WT, independent of gender. Sodium nitroprusside was not different between groups. The effect of the altered intrauterine environment on the development of abnormal vascular function was limited at 7 wk of age and most evident at 14 wk; further deterioration was limited to ANG-mediated vascular contractility in KO offspring. Our findings provide some hope that at least the first seven postnatal weeks may be an appropriate therapeutic window to prevent cardiovascular disease later in life.
authors.affiliation: Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TexasTX 77555, USA. gichioss@utmb.edu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiossi
authors.forename: Maged M
authors.initials: MM
authors.lastname: Costantine
authors.forename: Esther
authors.initials: E
authors.lastname: Tamayo
authors.forename: Phyllis
authors.initials: P
authors.lastname: Orise
authors.forename: Gary D V
authors.initials: GD
authors.lastname: Hankins
authors.forename: George R
authors.initials: GR
authors.lastname: Saade
authors.forename: Monica
authors.initials: M
authors.lastname: Longo
mesh_terms: D000367:Age Factors; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000196:embryology / Q000201:enzymology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000196:embryology / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D047109:Fetal Development; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D010927:Placental Insufficiency / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011247:Pregnancy; D012737:Sex Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse