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(Circulation Research. 2008;103:1018.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Overexpression of Vascular Endothelial Growth Factor-B in Mouse Heart Alters Cardiac Lipid Metabolism and Induces Myocardial Hypertrophy

Terhi Karpanen^*, Maija Bry^*, Hanna M. Ollila, Tuulikki Seppänen-Laakso, Erkki Liimatta, Hanna Leskinen, Riikka Kivelä, Teemu Helkamaa, Mari Merentie, Michael Jeltsch, Karri Paavonen, Leif C. Andersson, Eero Mervaala, Ilmo E. Hassinen, Seppo Ylä-Herttuala, Matej Orei, Kari Alitalo

From the Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, and Department of Pathology, Haartman Institute (T.K., M.B., H.O., R.K., M.J., K.P., K.A.) and Institute of Biomedicine (T.H., E.M.), Department of Pharmacology, University of Helsinki and Helsinki University Central Hospital; VTT Technical Research Centre of Finland (T.S.-L., M.O.), Espoo; Departments of Medical Biochemistry and Molecular Biology (E.L., I.E.H.) and Pharmacology and Toxicology (H.L.), University of Oulu; A. I. Virtanen Institute (M.M., S.Y.-H.), Department of Biotechnology and Molecular Medicine, University of Kuopio; and Department of Pathology (L.C.A.), Haartman Institute, University of Helsinki, Finland. Present address for T.K.: Hubrecht Institute, Utrecht, The Netherlands.

Correspondence to Kari Alitalo, MD, PhD, Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, PO Box 63, FI-00014 Helsinki, Finland. E-mail kari.alitalo{at}helsinki.fi

Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the -myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II–induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor.

Key Words: VEGF-B • cardiac hypertrophy • cardiac metabolism • fatty acids • mitochondria

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