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 Oresic, Kari Alitalo (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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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 α-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.
Original languageEnglish
Pages (from-to)1018-1026
Number of pages9
JournalCirculation Research
Volume103
Issue number9
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

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Lipid Metabolism
Hypertrophy
Vascular Endothelial Growth Factor B
Cardiomegaly
Cardiac Myocytes
Transgenic Mice
Myosin Heavy Chains
Angiogenesis Inducing Agents
Ceramides
Angiotensins
Vacuoles
mouse vascular endothelial growth factor B
Cell Nucleus
Transgenes
Blood Vessels
Intercellular Signaling Peptides and Proteins
Mitochondria
Triglycerides
Ischemia
Heart Rate

Keywords

  • VEGF-B
  • cardiac hypertrophy
  • cardiac metabolism
  • fatty acids
  • mitochondria

Cite this

Karpanen, Terhi ; Bry, Maija ; Ollila, Hanna M. ; Seppänen-Laakso, Tuulikki ; Liimatta, Erkki ; Leskinen, Hanna ; Kivelä, Riikka ; Helkamaa, Teemu ; Merentie, Mari ; Jeltsch, Michael ; Paavonen, Karri ; Andersson, Leif C. ; Mervaala, Eero ; Hassinen, Ilmo E. ; Ylä-Herttuala, Seppo ; Oresic, Matej ; Alitalo, Kari. / Overexpression of Vascular Endothelial Growth Factor-B in Mouse Heart Alters Cardiac Lipid Metabolism and Induces Myocardial Hypertrophy. In: Circulation Research. 2008 ; Vol. 103, No. 9. pp. 1018-1026.
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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 α-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.",
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author = "Terhi Karpanen and Maija Bry and Ollila, {Hanna M.} and Tuulikki Sepp{\"a}nen-Laakso and Erkki Liimatta and Hanna Leskinen and Riikka Kivel{\"a} and Teemu Helkamaa and Mari Merentie and Michael Jeltsch and Karri Paavonen and Andersson, {Leif C.} and Eero Mervaala and Hassinen, {Ilmo E.} and Seppo Yl{\"a}-Herttuala and Matej Oresic and Kari Alitalo",
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doi = "10.1161/CIRCRESAHA.108.178459",
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Karpanen, T, Bry, M, Ollila, HM, Seppänen-Laakso, T, Liimatta, E, Leskinen, H, Kivelä, R, Helkamaa, T, Merentie, M, Jeltsch, M, Paavonen, K, Andersson, LC, Mervaala, E, Hassinen, IE, Ylä-Herttuala, S, Oresic, M & Alitalo, K 2008, 'Overexpression of Vascular Endothelial Growth Factor-B in Mouse Heart Alters Cardiac Lipid Metabolism and Induces Myocardial Hypertrophy', Circulation Research, vol. 103, no. 9, pp. 1018-1026. https://doi.org/10.1161/CIRCRESAHA.108.178459

Overexpression of Vascular Endothelial Growth Factor-B in Mouse Heart Alters Cardiac Lipid Metabolism and Induces Myocardial Hypertrophy. / Karpanen, Terhi; Bry, Maija; Ollila, Hanna M.; Seppänen-Laakso, Tuulikki; Liimatta, Erkki; Leskinen, Hanna; Kivelä, Riikka; Helkamaa, Teemu; Merentie, Mari; Jeltsch, Michael; Paavonen, Karri; Andersson, Leif C.; Mervaala, Eero; Hassinen, Ilmo E.; Ylä-Herttuala, Seppo; Oresic, Matej; Alitalo, Kari (Corresponding Author).

In: Circulation Research, Vol. 103, No. 9, 2008, p. 1018-1026.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Overexpression of Vascular Endothelial Growth Factor-B in Mouse Heart Alters Cardiac Lipid Metabolism and Induces Myocardial Hypertrophy

AU - Karpanen, Terhi

AU - Bry, Maija

AU - Ollila, Hanna M.

AU - Seppänen-Laakso, Tuulikki

AU - Liimatta, Erkki

AU - Leskinen, Hanna

AU - Kivelä, Riikka

AU - Helkamaa, Teemu

AU - Merentie, Mari

AU - Jeltsch, Michael

AU - Paavonen, Karri

AU - Andersson, Leif C.

AU - Mervaala, Eero

AU - Hassinen, Ilmo E.

AU - Ylä-Herttuala, Seppo

AU - Oresic, Matej

AU - Alitalo, Kari

PY - 2008

Y1 - 2008

N2 - 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 α-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.

AB - 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 α-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.

KW - VEGF-B

KW - cardiac hypertrophy

KW - cardiac metabolism

KW - fatty acids

KW - mitochondria

U2 - 10.1161/CIRCRESAHA.108.178459

DO - 10.1161/CIRCRESAHA.108.178459

M3 - Article

VL - 103

SP - 1018

EP - 1026

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

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ER -