Abstract: Objective To investigate the role of VEGFB gene in the progression of atherosclerosis through establishing an ApoE^-/-/VEGFB^-/- mouse model.Methods There were four groups in the current experiment: a high-lipid diet ApoE^-/-/VEGFB^-/- group (WD-ApoE^-/-/VEGFB^-/-), a common diet ApoE^-/-/VEGFB^-/- group (Chow-ApoE^-/-/VEGFB^-/-), a high-lipid diet ApoE^-/- group (WD-ApoE^-/-) and a common diet ApoE^-/- group (Chow-ApoE^-/-). The mice were weighed every week, and their changes in blood lipids were measured. The aortas were stained with oil Red O, and the hearts were collected, cut into frozen sections and stained with oil Red O and H-E to analyze the changes of plaque deposition in the aorta of the mice.Results The WD-ApoE^-/-/VEGFB^-/- group showed remarkable increases in body weight, total cholesterol, triglyceride, and low-density lipoprotein, compared with the WD-ApoE^-/- group. According to the oil red O staining, increased lipid plaque areas were observed in the aorta of ApoE^-/-/VEGFB^-/- mice, compared with ApoE^-/- mice. Frozen sections also indicated enlarged lipid plaque area in the aorta root of ApoE^-/-/VEGFB^-/- mice, compared with ApoE^-/- mice. HE staining confirmed increased necrotic area in the aortic root of ApoE^-/-/VEGFB^-/- mice, compared with ApoE^-/- mice.Conclusions VEGFB^-/- can effectively increase the deposition of aortic lipid plaque, enlarge necrotic area, and promote the progression of atherosclerosis.