Effect of Platelet-Derived Growth Factor Receptor-α and -β Blockade on Flow-Induced Neointimal Formation in Endothelialized Baboon Vascular Grafts

Abstract

Abstract —The growth of neointima and neointimal smooth muscle cells in baboon polytetrafluoroethylene grafts is regulated by blood flow. Because neointimal smooth muscle cells express both platelet-derived growth factor receptor-α and -β (PDGFR-α and -β), we designed this study to test the hypothesis that inhibiting either PDGFR-α or PDGFR-β with a specific mouse/human chimeric antibody will modulate flow-induced neointimal formation. Bilateral aortoiliac grafts and distal femoral arteriovenous fistulae were placed in 17 baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, normalizing flow through the ipsilateral graft while maintaining high flow in the contralateral graft. The experimental groups received a blocking antibody to PDGFR-α (Ab-PDGFR-α; 10 mg/kg; n=5) or PDGFR-β (Ab-PDGFR-β; 10 mg/kg; n=6) by pulsed intravenous administration 30 minutes before ligation and at 4, 8, 15, and 22 days after ligation. Controls received carrier medium alone (n=8). Serum antibody concentrations were followed. Grafts were harvested after 28 days and analyzed by videomorphometry. Serum Ab-PDGFR-α concentrations fell rapidly after day 7 to 0, whereas serum Ab-PDGFR-β concentrations were maintained at the target levels (>50 μg/mL). Compared with controls (3.7±0.3), the ratio of the intimal areas (normalized flow/high flow) was significantly reduced in Ab-PDGFR-β (1.2±0.2, P <0.01) but not in Ab-PDGFR-α (2.2±0.4). Ab-PDGFR-α decreased significantly the overall smooth muscle cell nuclear density of the neointima ( P <0.01) compared with either the control or Ab-PDGFR-β treated groups. PDGFR-β is necessary for flow-induced neointimal formation in prosthetic grafts. Targeting PDGFR-β may be an effective pharmacological strategy for suppressing graft neointimal development.