title: Uterine artery remodeling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice.
abstract: The progressive rise in uterine blood flow during pregnancy is accompanied by outward hypertrophic remodeling of the uterine artery (UA). This process involves changes of the arterial smooth muscle cells and extracellular matrix. Acute increases in blood flow stimulate endothelial production of nitric oxide (NO). It remains to be established whether endothelial NO synthase (eNOS) is involved in pregnancy-related arterial remodeling. We tested the hypothesis that absence of eNOS results in a reduced remodeling capacity of the UA during pregnancy leading to a decline in neonatal outcome. UA of nonpregnant and pregnant wild-type (Nos3+/+) and eNOS-deficient (Nos3-/-) mice were collected and processed for standard morphometrical analyses. In addition, cross sections of UA were processed for cytological (smoothelin, smooth muscle alpha-actin) and proliferation (Ki-67) immunostaining. We compared the pregnancy-related changes longitudinally and, together with the data on pregnancy outcome, transversally by analysis of variance with Bonferroni correction. During pregnancy, the increases in radius and medial cross sectional area of Nos3-/- UA was significantly less than those of Nos3+/+ UA. Smooth muscle cell dedifferentiation and proliferation were impaired in gravid Nos3-/- mice as deduced from the lack of change in the expression of smoothelin and smooth muscle alpha-actin, and the reduced Ki-67 expression. Until 17 days of gestation, litter size did not differ between both genotypes, but at birth the number of viable newborn pups and their weights were smaller in Nos3-/- than in Nos3+/+ mice. We conclude that absence of eNOS adversely affects UA remodeling in pregnancy, which may explain the impaired pregnancy outcome observed in these mice.
authors.affiliation: Department of Obstetrics and Gynecology, University of Maastricht, The Netherlands.
authors.forename: Olivier W H
authors.initials: OW
authors.lastname: van der Heijden
authors.forename: Yvonne P G
authors.initials: YP
authors.lastname: Essers
authors.forename: Gregorio
authors.initials: G
authors.lastname: Fazzi
authors.forename: Louis L H
authors.initials: LL
authors.lastname: Peeters
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
authors.forename: Guillaume J J M
authors.initials: GJ
authors.lastname: van Eys
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn; D001158:Arteries / Q000033:anatomy & histology / Q000201:enzymology / Q000502:physiology; D005260:Female; D005865:Gestational Age; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011247:Pregnancy; D011256:Pregnancy Outcome; D012098:Reproduction; D014599:Uterus / Q000098:blood supply* / Q000201:enzymology*
chemical_list: D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse