Short and long-term effects of hVEGF-A(165) in Cre-activated transgenic mice.
We have generated a transgenic mouse where hVEGF-A(165) expression has been silenced with loxP-STOP fragment, and we used this model to study the effects of hVEGF-A(165) over-expression in mice after systemic adenovirus mediated Cre-gene transfer. Unlike previous conventional transgenic models, this model leads to the expression of hVEGF-A(165) in only a low number of cells in the target tissues in adult mice. Levels of hVEGF-A(165) expression were moderate and morphological changes were found mainly in the liver, showing typical signs of active angiogenesis. Most mice were healthy without any major consequences up to 18 months after the activation of hVEGF-A(165) expression. However, one mouse with a high plasma hVEGF-A(165) level died spontaneously because of bleeding into abdominal cavity and having liver hemangioma, haemorrhagic paratubarian cystic lesions and spleen peliosis. Also, two mice developed malignant tumors (hepatocellular carcinoma and lung adenocarcinoma), which were not seen in control mice. We conclude that long-term uncontrolled hVEGF-A(165) expression in only a limited number of target cells in adult mice can be associated with pathological changes, including possible formation of malignant tumors and uncontrolled bleeding in target tissues. These findings have implications for the design of long-term clinical trials using hVEGF-A(165) gene and protein.
Leppänen
Pia
P
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Finland.
Kholová
Ivana
I
Mähönen
Anssi J
AJ
Airenne
Kari
K
Koota
Suvi
S
Mansukoski
Hannu
H
Närväinen
Johanna
J
Wirzenius
Maria
M
Alhonen
Leena
L
Jänne
Juhani
J
Alitalo
Kari
K
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A