The role of alpha and beta platelet-derived growth factor receptor in the vascular response to injury in nonhuman primates

Restenosis remains a significant clinical problem associated with mechanica l interventional procedures for arterial revascularization or repair, inclu ding coronary angioplasty and stenting. Studies with rodents have establish ed that platelet-derived growth factor (PDGF), a potent chemotactic and mit ogenic agent for vascular smooth muscle cells, is a key mediator of lesion formation alter vascular injury. To further explore this hypothesis in a mo re clinically relevant model, neutralizing monoclonal antibodies (mAbs) wer e used to examine the effect of selective inhibition of alpha or beta PDGF receptor (PDGFR) on neointima formation in nonhuman primates. Carotid arter ies were injured by surgical endarterectomy and femoral arteries by balloon catheter dilatation. Immunostaining revealed that, both injuries induced c ell proliferation and the upregulation of beta PDGFR but not alpha PDGFR. B y 7 days after injury, beta PDGFR staining was limited to the luminal regio n of the media, the small areas of neointima, and the adventitia. Nearly al l bromodeoxyuridine-positive cells were found in these regions as well. Aft er 30 days, a concentric neointima that stained strongly for beta PDGFR had formed in the carotid and femoral arteries. Treatment of baboons with anti -beta PDGFR mAb 2A1E2 for 6 days after injury reduced the carotid artery an d femoral artery lesion sizes by 37% (P<0.05) and 48% (P<0.005), respective ly, when measured at 30 days. Under the same conditions, treatment with ant i-alpha PDGFR mAb 2H7C5 had no effect. These findings suggest that PDGF med iates neointima formation through the beta PDGFR, and that antagonism of th is pathway may be a promising therapeutic strategy for reducing clinical re stenosis.