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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1845.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice

Tina Raj; Peter Kanellakis; Giovanna Pomilio; Garry Jennings; Alex Bobik; Alex Agrotis

From the Baker Heart Research Institute, Melbourne, Victoria, Australia.

Correspondence to Dr Alex Agrotis, Cell Biology Laboratory, Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail alex.agrotis{at}baker.edu.au

Objective— To determine the significance of fibroblast growth factor receptor (FGFR) expression for the development of atherosclerotic lesions in apoE-deficient (apoE^–/–) mice.

Methods and Results— ApoE^–/– mice fed a high-fat diet were administered the FGFR tyrosine kinase inhibitor SU5402 (25 mg/kg/d sc), which inhibited neointima growth by 85%. We measured its effects on lesion size at the aortic sinus, macrophage and smooth muscle cell (SMC) accumulation, the expression of monocyte chemotactic and retention factors, as well as its effects on FGFR expression/phosphorylation. FGFR tyrosine kinase inhibition reduced phosphorylated FGFRs in lesions by 90%, associated with a 65% reduction in lesion size measured using Oil Red O. Macrophages and SMCs within lesions were reduced by 58% and 78%, respectively. Monocyte chemotactic protein-1 (MCP-1) expression was also reduced, as was the expression of hyaluronan synthase, cyclooxygenase-2, CD36, and endothelial monocyte-activating polypeptide-II. Although 3 FGFR types were expressed in lesions, the effects of SU5402 could be attributed largely to inhibition of FGFR-1 phosphorylation.

Conclusions— Atherosclerotic lesions in apoE^–/– mice express multiple FGFRs and an active FGF:FGFR-1 signaling system that promotes atherosclerosis development via increased SMC proliferation, and by augmenting macrophage accumulation via increased expression of MCP-1 and factors promoting macrophage retention in lesions.

To assess the significance of fibroblast growth factors (FGFs) and their receptors (FGFRs) for atherosclerosis, we inhibited this system in apoE^–/– mice. Such inhibition markedly reduced smooth muscle cell and macrophage accumulation, attenuated atherosclerotic lesion severity, and greatly reduced FGFR-1 phosphorylation. Thus, FGF:FGFR-1 signaling promotes the development of atherosclerotic lesions.

Key Words: apoE^–/– mice • atherosclerosis • fibroblast growth factor receptors • proliferation • macrophage retention

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