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

Abstract

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 (1×10 9 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.

Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer

“…Thus, it seems pertinent to conclude that gene therapy causing transient VEGF expression does not induce the progression of either atherosclerosis or CAD. 20 Even though malignant diseases had caused most of the chronic morbidities in patients participating in the trial, the incidence of cancer was not increased significantly in the VEGF groups. All malignancies were diagnosed more than 2 years after the gene transfer.…”

Increased Atherosclerotic Lesion Calcification in a Novel Mouse Model Combining Insulin Resistance, Hyperglycemia, and Hypercholesterolemia

“…This finding is in line with other studies performed with the LDLR Ϫ/Ϫ ApoB 100/100 model. 20,21 Hypercholesterolemia induced by Western diet clearly thickened the plaques in both groups and led to the development of more advanced lesions with macrophage infiltrates and large necrotic areas covered by a fibrous cap. Nevertheless, the observed association between en face lesion area and fed state insulin level in the IGF-II/LDLR Ϫ/Ϫ ApoB 100/100 mice supports the proatherogenic effect of the prediabetic state.…”

Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

“…These findings indicate that VEGFR2 activity plays an important role in the development of atherosclerosis, a chronic inflammatory disease of the vessel wall. Moreover, VEGF delivery induces the progression of atherosclerotic plaque by promoting leukocyte recruitment and neovascularization in cholesterol-fed rabbits and in apoE-or apoE/apoB100-deficient mice (6,7,18,21), although a disparate result has been reported (19). VEGF is absent in healthy human arteries but is strongly expressed in early and advanced atherosclerotic lesions, and the degree of its expression increases with severity of atherosclerosis (14,22).…”