Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy.

Abstract

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 alpha-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.

• Authors: 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 Oresic, Kari Alitalo
• Journal: Circulation research (Circ Res) Vol. 103 Issue 9 Pg. 1018-26 (Oct 24 2008) ISSN: 1524-4571 [Electronic] United States
• PMID: 18757827 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ceramides
• Triglycerides
• VEGFB protein, human
• Vascular Endothelial Growth Factor B
• Angiotensin II
• Ventricular Myosins
• Myosin Heavy Chains

Topics

• Angiotensin II
• Animals
• Blood Pressure
• Capillaries (metabolism, pathology)
• Cardiomegaly (metabolism, pathology, physiopathology)
• Cardiomyopathies (metabolism, pathology, physiopathology)
• Cell Size
• Ceramides (metabolism)
• Coronary Vessels (metabolism, pathology)
• Disease Models, Animal
• Heart Rate
• Humans
• Hypertension (chemically induced, genetics, physiopathology)
• Lipid Metabolism
• Mice
• Mice, Transgenic
• Mitochondria, Heart (metabolism, pathology)
• Myocardial Ischemia (metabolism, physiopathology)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism)
• Myosin Heavy Chains (genetics)
• Neovascularization, Physiologic
• Oxidation-Reduction
• Promoter Regions, Genetic
• Skin (blood supply, metabolism)
• Time Factors
• Triglycerides (metabolism)
• Up-Regulation
• Vascular Endothelial Growth Factor B (genetics, metabolism)
• Ventricular Function, Left
• Ventricular Myosins (genetics)