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Smooth Muscle-Targeted Overexpression of Insulin-Like Growth Factor I Results in Enhanced Vascular Contractility

Departments of Molecular and Cellular Physiology, and Endocrinology and Metabolism, University of Cincinnati, Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: James A. Fagin, M.D., Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, Ohio 45267. E-mail: faginja{at}uc.edu

Insulin-like growth factor I (IGF-I) has been postulated to function as a vasodilator. We explored the vasoactive effects of chronic elevations of arterial IGF-I levels in SMP8-IGF-I mice, in which IGF-I is overexpressed in smooth muscle (SM) by means of a SM -actin promoter. Denuded aortas from SMP8-IGF-I mice generated increased force in response to KCl or phenylephrine and had greater sensitivity to KCl depolarization. This is not due to desensitization of a SM NO pathway, as pretreatment with n--nitro-L-arginine affected both wild-type and SMP8-IGF-I aortas to a similar degree. The increased contractility ex vivo is not associated with changes in heart rate or blood pressure. Total smooth muscle myosin heavy chain (SMHC) messenger RNA (mRNA) was greater in SMP8-IGF-I aortas, with preferential expression of SMHC-A. Reciprocal effects on contractility and SMHC mRNA were observed in SMP8-IGFBP-4 animals, in which IGF-binding protein-4 was overexpressed through the same promoter. Also, SM -actin mRNA was increased in the aortas from SMP8-IGF-I mice. In summary, chronic arterial overexpression of IGF-I is associated with increased contractility. These effects differ from those seen after acute exposure to the growth factor and may relate to IGF-mediated changes in expression and relative isoform abundance of critical contractile proteins.

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