Adenovirus-Mediated Gene Transfer of Macrophage Colony Stimulating Factor to the Arterial Wall In Vivo

From the Divisions of Endocrinology and Metabolism (T.O'B.) and of Cardiovascular Disease (I.K.), the Division of Vascular Surgery (G.M., T.M., P.G., S.M.), and the Division of Anatomic Pathology (T.B.C.), The Mayo Clinic, Rochester, Minn; The Gladstone Institute of Cardiovascular Disease, University of California, San Francisco (J.T.); and the Department of Microbiology and Immunology, Pennsylvania State University, Hershey, Pa (D.S.).

Correspondence to Timothy O'Brien, MD, Division of Endocrinology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail Obrien.timothy{at}mayo.edu

Abstract—Macrophage colony stimulating factor (MCSF) is believed to play a key role in one of the earliest events in atherosclerosis, ie, monocyte to macrophage differentiation in the arterial intima. The aim of this study was to examine the biological effects of vascular wall expression of MCSF. A recombinant adenovirus vector encoding human MCSF (AdMCSF) was generated by standard techniques of homologous recombination in 293 cells. The rabbit carotid artery was transduced with AdMCSF. As negative controls, carotid arteries were transduced with either an adenoviral vector encoding ß-galactosidase, an adenoviral vector encoding apolipoprotein E, or diluent alone. Intima-media thickness ratio was calculated 5 and 21 days after transduction. The cell type present in intimal infiltrates was analyzed by immunohistochemistry. MCSF expression was demonstrated in the vessel wall of AdMCSF-transduced vessels by reverse transcription–polymerase chain reaction and immunofluorescence. In contrast to control vessels, adenovirus-mediated MCSF expression was associated with an intimal cellular infiltrate consisting of smooth muscle cells and small numbers of macrophages. Whereas the intima-media thickness ratio was greater in AdMCSF-transduced vessels at 5 days, this difference was no longer statistically significant at 21 days. These results suggest that MCSF may play a role in recruitment of monocytes and macrophages to the vessel wall and may contribute to smooth muscle cell proliferation and migration.

Key Words: macrophage colony stimulating factor • monocytes • atherosclerosis • gene transfer • smooth muscle cells

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