Effect of platelet-derived growth factor receptor-alpha and -beta blockadeon flow-induced neointimal formation in endothelialized baboon vascular grafts

The growth of neointima and neointimal smooth muscle cells in baboon polyte trafluoroethylene grafts is regulated by blood flow. Because neointimal smo oth muscle cells express both platelet-derived growth factor receptor-cy an d -beta (PDGFR-alpha and -beta), we designed this study to test the hypothe sis that inhibiting either PDGFR-alpha or PDCFR-beta with a specific mouse/ human chimeric antibody will modulate flow-induced neointimal formation. Bi lateral aortoiliac grafts and distal femoral arteriovenous fistulae were pl aced in 17 baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, no rmalizing flow through the ipsilateral graft while maintaining high flow in the contralateral graft. The experimental groups received a blocking antib ody to PDGFR-alpha (Ab-PDGFR-alpha; 10 mg/kg; n=5) or PDGFR-beta (Ab-PDGFR- beta; 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 ca rrier medium alone (n=8). Serum antibody concentrations were followed. Graf ts were harvested after 28 days and analyzed by videomorphometry. Serum Ab- PDGFR-alpha concentrations fell rapidly after day 7 to 0, whereas serum Ab- PDGFR-beta concentrations were maintained at the target levels (>50 mu g/mL ). Compared with controls (3.7+/-0.3), the ratio of the intimal areas (norm alized flow/high flow) was significantly reduced in Ab-PDGFR-beta (1.2+/-0. 2, P<0.01) but not in Ab-PDGFR-alpha (2.2+/-0.4). Ab-PDGFR-alpha decreased significantly the overall smooth muscle cell nuclear density of the neointi ma (P<0.01) compared with either the control or Ab-PDGFR-beta treated group s. PDGFR-beta is necessary for flow-induced neointimal formation in prosthe tic grafts. Targeting PDGFR-beta may be an effective pharmacological strate gy for suppressing graft neointimal development.