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Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: new tricks for old dogs?

Chandike M. Mallawaarachchi^*, Peter L. Weissberg^* and Richard C. M. Siow^*,,1

^* Division of Cardiovascular Medicine, School of Clinical Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK; and

Cardiovascular Division, School of Biomedical and Health Sciences, King’s College London, Guy’s Hospital Campus, London, UK

¹Correspondence: Cardiovascular Division, School of Biomedical and Health Sciences, Kings College London, Guys Hospital Campus, London SE1 1UL, UK. E-mail: richard.siow{at}kcl.ac.uk

ABSTRACT

Migration of adventitial fibroblasts contributes to vascular remodeling after angioplasty. This study has used perivascular gene transfer of a truncated platelet-derived growth factor PDGF receptor (PDGFXR) to investigate whether antagonism of PDGF signaling alters adventitial cell migration after balloon injury in rat carotid arteries. Adenoviruses coordinating expression of ß-galactosidase (LacZ) and PDGFXR or LacZ and green fluorescent protein (GFP) were applied to the perivascular surface of arteries and balloon injury performed 4 days later. Vessels were excised at 3, 7, and 14 days to determine morphology and gene expression. Uninjured arteries only expressed LacZ positive cells in the adventitial compartment; however, after injury in LacZ and GFP transfected arteries, LacZ positive cells contributed to the population of cells within the media and neointima at 7–14 days. Overexpression of PDGFXR and LacZ resulted in a significant reduction in the number of LacZ labeled cells in the neointima after vascular injury, concomitant with reduced remodeling, collagen content, expression of matrix metalloproteinase-2, and increased levels of tissue inhibitors of metalloproteinase-1 and -2. We provide evidence that perivascular antagonism of PDGF attenuates remodeling and contribution of adventitial fibroblasts to neointima formation after balloon angioplasty. Perivascular gene transfer may represent a therapeutic strategy to reduce the incidence of restenosis.—Mallawaarachchi, C. M., Weissberg, P. L., and Siow, R. C. M. Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: New tricks for old dogs?

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