Effect of Platelet-Derived Growth Factor Receptor-α and -β Blockade on Flow-Induced Neointimal Formation in Endothelialized Baboon Vascular Grafts
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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.
- Received September 16, 1999.
- Accepted January 11, 2000.
- © 2000 American Heart Association, Inc.