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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2050.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis

Arnaud D. Hauer; Gijs H.M. van Puijvelde; Niels Peterse; Paula de Vos; Vincent van Weel; Eva J.A. van Wanrooij; Erik A.L. Biessen; Paul H.A. Quax; Andreas G. Niethammer; Ralph A. Reisfeld; Theo J.C. van Berkel; Johan Kuiper

From the Division of Biopharmaceutics (A.D.H., G.H.M.P., N.P., P.d.V., E.J.A.v.W., E.A.L.B., T.J.C.v.B., J.K.), Leiden University, The Netherlands; the Department of Biosciences, TNO Quality of Life, Gaubius Laboratory, and the Department of Vascular Surgery (V.v.W., P.H.A.Q.), LUMC, Leiden, the Netherlands; the Department of Radiation Oncology (A.G.N.), Heidelberg School of Medicine, Heidelberg, Germany; and The Scripps Research Institute (R.A.R.), La Jolla, Calif.

Correspondence to Dr A.D. Hauer, LACDR, Division of Biopharmaceutics, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail A.Hauer{at}LACDR.leidenuniv.nl

Objective— Vascular endothelial growth factor receptor 2 (VEGFR2)–overexpressing cells may form an interesting target for the treatment of atherosclerosis because of their involvement in processes that contribute to this disease, such as angiogenesis.

Methods and Results— We vaccinated mice against VEGFR2 by an orally administered DNA vaccine, comprising a plasmid, encoding murine VEGFR2, carried by live attenuated Salmonella typhimurium. This vaccine induces cellular immunity against cells that overexpress VEGFR2. Vaccination of hypercholesterolemic mice against VEGFR2 resulted in a marked induction of CD8⁺ cytotoxic T cells specific for VEGFR2 and led to an inhibition of angiogenesis in a hindlimb ischemia model. Interestingly, VEGFR2 vaccination attenuated the progression of preexisting advanced atherosclerotic lesions in the brachiocephalic artery of apoE^–/– mice. Furthermore, VEGFR2 vaccination strongly reduced the initiation of collar-induced atherosclerosis in the carotid arteries of LDLr^–/– mice. In addition, denudation of the carotid artery, as a model for postinterventional lesion formation, resulted in delayed endothelial replacement and significantly increased neointima formation on VEGFR2 vaccination.

Conclusions— These data indicate the prominent role of VEGFR2⁺ cells in cardiovascular diseases and show that induction of cellular immunity against atherosclerosis-associated cells by means of DNA vaccination may contribute to the development of novel therapies against atherosclerosis.

Induction of cellular immunity against VEGFR2⁺ cells by DNA vaccination blocked angiogenesis and attenuated both initiation and progression of atherosclerosis, whereas postinterventional neointima formation was enhanced indicating the prominent role of VEGFR2⁺ cells in cardiovascular diseases and showing the possibilities of DNA vaccination in the protection against atherosclerosis.

Key Words: atherosclerosis • restenosis • vaccination • angiogenesis • VEGFR2⁺ cells

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