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Undernutrition in Utero Augments Systolic Blood Pressure and Cardiac Remodeling in Adult Mouse Offspring: Possible Involvement of Local Cardiac Angiotensin System in Developmental Origins of Cardiovascular Disease

Department of Gynecology and Obstetrics (M.K., H.I., S.Y., H.Mo., S.F.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Departments of Etiology and Pathology (S.-I.S.) and Atherosclerosis and Diabetes (H.Ma., Y.M., Y.Y.), National Cardiovascular Center, Suita, Osaka 565-8565, Japan; Department of Obstetrics and Gynecology (N.S.), Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; and Precursory Research for Embryonic Science and Technology (PRESTO) (S.Y.), Japan Science and Technology Agency (JST), Kawaguchi City, Saitama 332-0012, Japan

Address all correspondence and requests for reprints to: Hiroaki Itoh, Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: ihiroaki{at}kuhp.kyoto-u.ac.jp.

Evidence has emerged that undernutrition in utero is a risk factor for cardiovascular disorders in adulthood, along with genetic and environmental factors. Recently, the local expression of angiotensinogen and related bioactive substances has been demonstrated to play a pivotal role in cardiac remodeling, i.e. fibrosis and hypertrophy. The aim of the present study was to clarify the possible involvement of the local cardiac angiotensin system in fetal undernutrition-induced cardiovascular disorders. We developed a mouse model of undernutrition in utero by maternal food restriction, in which offspring (UN offspring) showed an increase in systolic blood pressure (8 wk of age, P < 0.05; and 16 wk, P < 0.01), perivascular fibrosis of the coronary artery (16 wk, P < 0.05) and cardiac cardiomegaly (16 wk, P < 0.01), and cardiomyocyte enlargement, concomitant with a significant augmentation of angiotensinogen (P < 0.05) and endothelin-1 (P < 0.01) mRNA expression and a tendency to increase in immunostaining for both angiotensin II and endothelin-1 in the left ventricles (16 wk). These findings suggest that fetal undernutrition activated the local cardiac angiotensin system-associated bioactive substances, which contributed, at least partly, to the development of cardiac remodeling in later life, in concert with the effects of increase in blood pressure.