Cardiovascular Research 56 (2002) 145–153 www.elsevier.com / locate / cardiores Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring a a a ´ Maria do Carmo P. Franco , Roberia Maria M.P. Arruda , Ana PaulaVillela Dantas , b a b Elisa Mitiko Kawamoto , Zuleica B. Fortes , Cristoforo Scavone , a a a, * Maria Helena C. Carvalho , Rita C.A. Tostes , Dorothy Nigro a ˜ Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, 05508-900, ˜ Av. Prof Lineu Prestes, 1524 —Sao Paulo, SP , Brazil b ˜ Laboratory of Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, 05508-900, ˜ Av. Prof Lineu Prestes, 1524 —Sao Paulo, SP , Brazil Received 10 October 2001; accepted 30 May 2002 Abstract Objective: Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension in adulthood. In an attempt to define the mechanisms whereby blood pressure may be raised, we have hypothesized that arteries from offspring of nutritionally restricted dams exhibit abnormalities in the endothelial function and in nitric oxide synthesis. In order to investigate the existence of potential gender differences on the effects of intrauterine undernutrition, both male and female offspring of pregnant Wistar rats on normal and restricted diets were studied in adulthood. Methods: Female pregnant Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. At 14 weeks of age, the rats were used for the study of vascular reactivity, eNOS and iNOS gene expression, eNOS activity and, in the case of females, estrogen levels. Results: Intrauterine undernutrition induced hypertension in both male and female offspring, but hypertension was more severe in male rats. Endothelium-intact aortic rings from male and female rats in the restricted diet group exhibited increased responses to norepinephrine, decreased vasodilation to acetylcholine and unaltered responses to sodium nitroprusside in comparison to aortic rings from control rats. No gender-related differences were observed in the vascular reactivity studies. Intrauterine undernutrition promoted decreased gene expression for eNOS in aorta isolated from male, but not female, offspring, reduction in eNOS activity in both male and female offspring and impairment in synthesis of estrogen in female offspring. Conclusion: Our data show that intrauterine undernutrition: (1) induces hypertension both in the male and female offspring, hypertension being more severe in male than in female rats; (2) alters endothelium-dependent responses in aortas from the resulting offspring. The endothelial dysfunction is associated with a decrease in activity / expression of eNOS in aortas from male offspring. The mechanism involved in altered response to ACh in female offspring might be a consequence of reduction in estrogen levels leading to reduced eNOS activity.  2002 Elsevier Science B.V. All rights reserved. Keywords: Endothelial function; Gender; Hypertension; Nitric oxide 1. Introduction and predispose to the development of adulthood diseases [1]. Hypertension [2], coronary heart disease [3], type II Maternal undernutrition during critical periods of organ diabetes [4] and renal disease [5] are some of the disorders development is known to impair fetal growth and it has which have been linked to low birth weight. Whilst most of been suggested that endocrine or physiological changes these associations are based on retrospective population involved in the fetal adaptation to undernutrition persist studies, prospective investigations in animals are now providing substantial experimental evidence to support the *Corresponding author. Tel. / fax: 155-11-3091-7317. E-mail address: mdcfranco@yahoo.com (D. Nigro). Time for primary review 31 days. 0008-6363 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0008-6363(02)00508-4 by guest on May 28, 2016 Downloaded from