title: Effect of platelet-derived growth factor receptor-alpha and -beta blockade on flow-induced neointimal formation in endothelialized baboon vascular grafts.
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-alpha and -beta (PDGFR-alpha and -beta), we designed this study to test the hypothesis that inhibiting either PDGFR-alpha or PDGFR-beta 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-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 carrier medium alone (n=8). Serum antibody concentrations were followed. Grafts 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 microg/mL). Compared with controls (3.7+/-0.3), the ratio of the intimal areas (normalized 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 neointima (P<0.01) compared with either the control or Ab-PDGFR-beta treated groups. PDGFR-beta is necessary for flow-induced neointimal formation in prosthetic grafts. Targeting PDGFR-beta may be an effective pharmacological strategy for suppressing graft neointimal development.
authors.affiliation: Division of Vascular Surgery, University of Washington, Seattle, WA 98195-6410, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Davies
authors.forename: E L
authors.initials: EL
authors.lastname: Owens
authors.forename: D P
authors.initials: DP
authors.lastname: Mason
authors.forename: H
authors.initials: H
authors.lastname: Lea
authors.forename: P K
authors.initials: PK
authors.lastname: Tran
authors.forename: S
authors.initials: S
authors.lastname: Vergel
authors.forename: S A
authors.initials: SA
authors.lastname: Hawkins
authors.forename: C E
authors.initials: CE
authors.lastname: Hart
authors.forename: A W
authors.initials: AW
authors.lastname: Clowes
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta / Q000601:surgery; D017209:Apoptosis; D001166:Arteriovenous Shunt, Surgical; D001783:Blood Flow Velocity; D002455:Cell Division; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D005263:Femoral Artery / Q000601:surgery; D005268:Femoral Vein / Q000601:surgery; D006801:Humans; D006965:Hyperplasia; D007083:Iliac Artery / Q000601:surgery; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D009389:Neovascularization, Pathologic; D010215:Papio; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000166:cytology / Q000473:pathology / Q000502:physiology*
chemical_list: D000906:Antibodies; D011993:Recombinant Fusion Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta