Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: new tricks for old dogs?
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 beta-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
Chandike M
CM
Cardiovascular Division, School of Clinical Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.
Weissberg
Peter L
PL
Siow
Richard C M
RC
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D020212:Carotid Artery Injuries / Q000473:pathology / Q000628:therapy*; D002465:Cell Movement; D005347:Fibroblasts / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D007763:Lac Operon / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000008:administration & dosage* / Q000235:genetics; D017384:Sequence Deletion; D014018:Tissue Distribution; D014162:Transfection
D010982:Platelet-Derived Growth Factor; D049452:Green Fluorescent Proteins; D017479:Receptors, Platelet-Derived Growth Factor