Endothelium-specific overexpression of human vascular endothelial growth factor-D in mice leads to increased tumor frequency and a reduced lifespan

• Published in: The journal of gene medicine Vol. 14; no. 3; pp. 182 - 190
• Main Authors: Kotimaa, Antti A., Zainana, Anna-Mari, Pulkkinen, Eveliina, Huusko, Jenni, Heinonen, Suvi E., Kholová, Ivana, Stedt, Hanna, Lesch, Hanna P., Ylä-Herttuala, Seppo
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.2012; Wiley Periodicals Inc
• Subjects: Analysis of Variance; Animals; endothelium; Endothelium - metabolism; Gene therapy; Genetic Vectors - genetics; Hindlimb - blood supply; Hindlimb - pathology; Humans; Immunohistochemistry; ischemia; Ischemia - metabolism; Lentivirus; Mice; Mice, Transgenic; Neoplasms, Experimental - genetics; Neoplasms, Experimental - pathology; Promoter Regions, Genetic - genetics; Receptor, TIE-1 - genetics; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate; Transgenes - genetics; transgenesis; tumor; Vascular Endothelial Growth Factor D - genetics; Vascular Endothelial Growth Factor D - metabolism; VEGF-D
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.2608

Background Vascular endothelial growth factors (VEGFs) are central mediators in vascular development and lymphangiogenesis. VEGF‐D contributes to the growth and formation of blood and lymphatic vessels, although its biological role is still somewhat unclear. Methods Transgenic mice, which express the mature form of human VEGF‐D under endothelium‐specific Tie1 promoter, were produced by the lentiviral perivitelline‐injection method. The mice were followed up to generation F5 and the effect of the transgene was analyzed. Results Transgenic mice had a high expression of human (h)VEGF‐D in the endothelium in several tissues, such as kidney, liver, lung and spleen. However, transgenic mice developed tumors in lungs, kidneys, liver, mammary glands and lymph nodes upon aging and their mortality was also increased as a result of other pathological conditions. Hind limb ischemia was surgically induced in these mice and they were analyzed 1, 2 and 3 weeks after the ischemia operation. No significant differences were found in hVEGF‐D mRNA expression, the number of capillaries or tissue repair between ischemic transgenic mice and transgene negative littermates. Conclusions It is concluded that targeted unregulated long‐term expression of hVEGF‐D in endothelium may not be useful and reduces the life span of transgenic mice. Copyright © 2012 John Wiley & Sons, Ltd.