on June 28, 2007
Published online before print June 28, 2007, doi: 10.1161/ATVBAHA.107.143743
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Submitted on March 13, 2007
Accepted on June 4, 2007
Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis
Arnaud D. Hauer *;
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.
* To whom correspondence should be addressed. 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.
Key words: atherosclerosis • restenosis • vaccination • angiogenesis • VEGFR2+ cells
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