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VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-B, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits

Himadri Roy^*, Shalini Bhardwaj^*, Mohan Babu^*, Ilze Kokina^*, Sanna Uotila^*, Tiia Ahtialansaari^*, Teemu Laitinen, Juhana Hakumaki, Markku Laakso, Karl-Heinz Herzig^*, and Seppo Ylä-Herttuala^*,,,1

^* Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland;

Department of Medicine, University of Kuopio, Finland;

Gene Therapy Unit, Kuopio, University Hospital, Finland; and

Department of Biomedical NMR, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland

¹Correspondence: Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: seppo.ylaherttuala{at}uku.fi

ABSTRACT

Plaque angiogenesis may be associated with the development of unstable and vulnerable plaques. Vascular endothelial growth factors (VEGFs) are potent angiogenic factors that can affect plaque neovascularization. Our objective was to determine the effect of diabetes on atherosclerosis and on the expression of angiogenesis-related genes in atherosclerotic lesions. Alloxan was used to induce diabetes in male Watanabe heritable hyperlipidemic (WHHL) rabbits that were sacrificed 2 and 6 months after the induction of diabetes. Nondiabetic WHHL rabbits served as controls. Blood glucose (Glc), serum-free fatty acids (FFA), and serum triglyceride levels were significantly higher in diabetic rabbits. Accelerated atherogenesis was observed in the diabetic WHHL rabbits together with increased intramyocellular lipids (IMCL), as determined by ¹H-NMR spectroscopy. Atherosclerotic lesions in the diabetic rabbits had an increased content of macrophages and showed significant increases in immunostainings for vascular endothelial growth factor (VEGF)-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, RAGE, and NF-B. VEGF-A₁₆₅ and VEGFR-2 mRNA levels were significantly increased in aortas of the diabetic rabbits, where a trend toward increased plaque vascularization was also observed. These results suggest that diabetes accelerates atherogenesis, up-regulates VEGF-A, VEGF-D, and VEGF receptor-2 expression, and increases NF-B, RAGE, and inflammatory responses in atherosclerotic lesions in WHHL rabbits.—Roy, H., Bhardwaj, S., Babu, M., Kokina, I., Uotila, S., Ahtialansaari, T., Laitinen, T., Hakumaki, J., Laakso, M., Herzig, K-H., Ylä-Herttuala, S. VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-B, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits.

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