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(Circulation. 2005;112:1347-1352.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Gene Transfers of Vascular Endothelial Growth Factor-A, Vascular Endothelial Growth Factor-B, Vascular Endothelial Growth Factor-C, and Vascular Endothelial Growth Factor-D Have No Effects on Atherosclerosis in Hypercholesterolemic Low-Density Lipoprotein-Receptor/Apolipoprotein B48-Deficient Mice

Pia Leppänen, MSc; Suvi Koota, MSc; Ivana Kholová, MD, PhD; Jonna Koponen, MSc; Christina Fieber, MD; Ulf Eriksson, PhD; Kari Alitalo, MD, PhD; Seppo Ylä-Herttuala, MD, PhD, FESC

From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Finland (P.L., S.K., I.K., J.K., S.Y.-H.); the Departments of Medicine (S.Y.-H.) and the Gene Therapy Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland; the Ludwig Institute for Cancer Research (C.F., U.E.), Stockholm, Sweden; and the Cancer Biology Laboratory (K.A.), Biomedicum, University of Helsinki, Helsinki, Finland.

Correspondence to Seppo Ylä-Herttuala, MD, PhD, FESC, Professor of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail Seppo.Ylaherttuala{at}uku.fi

Received January 18, 2005; revision received April 19, 2005; accepted May 17, 2005.

Background— The role of vascular endothelial growth factors (VEGFs) in large arteries has been proposed to be either vasculoprotective or proatherogenic. Because VEGF family members are used for human therapy, it is important to know whether they could enhance atherogenesis. We tested the effects of the members of the VEGF gene family on atherogenesis in LDL-receptor/apolipoprotein (apo) B48 double-knockout (LDLR/apoB48) mice using systemic adenoviral gene transfer.

Methods and Results— Six groups of LDLR/apoB48-deficient mice (n=110) were kept 3 months on a Western-type diet. After 6 weeks of diet, mice were injected via tail vein with recombinant adenoviruses expressing VEGF-A, -B, -C, or -D or LacZ (1x10⁹ PFU) or rhVEGF-A protein (2 µg/kg) and euthanized 6 weeks later. Also, older mice (n=36) were injected after 4 months on the diet and euthanized 6 weeks later (total time on the diet, 22 weeks) to evaluate the effects of gene transfers on the development of more mature lesions. Aortas were analyzed for the presence of macroscopic lesions, cross-sectional lesion areas, neovascularization, and cellular composition of the lesions. All groups had equivalent plasma cholesterol and triglyceride levels. Gene transfers with recombinant adenoviruses or administration of rhVEGF-A protein had no statistically significant effects on en face atherosclerotic lesions in the aorta, cross-sectional lesion area, neovascularization, or cellular composition of the lesions.

Conclusions— This study shows no proatherogenic effects of adenovirus-mediated gene transfers of VEGF-A, -B, -C, or -D in the LDLR/apoB48-deficient hypercholesterolemic mice, in which lipoprotein profile and atherosclerosis closely resemble those in human disease.

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CLINICAL PERSPECTIVE

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