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This Article Full Text Full Text (PDF) All Versions of this Article: 72/5/1161    most recent biolreprod.104.033985v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van der Heijden, O. W.H. Articles by van Eys, G. J.J.M. Search for Related Content PubMed PubMed Citation Articles by van der Heijden, O. W.H. Articles by van Eys, G. J.J.M. Agricola Articles by van der Heijden, O. W.H. Articles by van Eys, G. J.J.M.

Uterine Artery Remodeling and Reproductive Performance Are Impaired in Endothelial Nitric Oxide Synthase-Deficient Mice¹

Department of Obstetrics and Gynecology,³ Molecular Genetics,⁴ Pharmacology and Toxicology⁵ and the Research Institutes GROW⁶ and CARIM,⁷ University of Maastricht, 6200 MD Maastricht, The Netherlands

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 -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 -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.

arterial remodeling, female reproductive tract, knockout mice, nitric oxide, pregnancy, uterine artery

² Correspondence: G.J.J.M. van Eys, Department of Molecular Genetics, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands. FAX: 31 43 388 4574; g.vaneys{at}gen.unimaas.nl

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