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Liver-Derived Insulin-Like Growth Factor-I Is Involved in the Regulation of Blood Pressure in Mice

Research Center for Endocrinology and Metabolism (Å.T., K.S., O.G.P.I., J.-O.J., C.O., J.I.), Department of Internal Medicine, Wallenberg Laboratory (E.B., R.M.), and Department of Clinical Physiology (K.C., G.B.), Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden; Department of Physiology (I.A., S.F., G.B.), University of Göteborg, S-405 30 Göteborg, Sweden; Department of Physiology and Pharmacology (O.S.), University of Southern Denmark, DK-5000 Odense C, Denmark; and Fraser Laboratories (J.-L.L.), Royal Victoria Hospital, McGill University, Montréal, Québec H3A 1A1, Canada

Address all correspondence and requests for reprints to: Åsa Tivesten, M.D., Research Center for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: asa.tivesten{at}medic.gu.se.

IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice. Echocardiography showed increased posterior wall thickness in combination with decreased stroke volume and cardiac output, whereas other systolic variables were unchanged, suggesting that these cardiac effects were secondary to increased peripheral resistance. Acute nitric oxide-synthase inhibition increased systolic BP more in LI-IGF-I-/- mice than in control mice. LI-IGF-I-/- mice showed impaired acetylcholine-induced vasorelaxation in mesenteric resistance vessels and increased levels of endothelin-1 mRNA in aorta. Thus, the increased peripheral resistance in LI-IGF-I-/- mice might be attributable to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice.

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