Effect of platelet-derived growth factor receptor-alpha and -beta blockade on flow-induced neointimal formation in endothelialized baboon vascular grafts.
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.
Davies
M G
MG
Division of Vascular Surgery, University of Washington, Seattle, WA 98195-6410, USA.
Owens
E L
EL
Mason
D P
DP
Lea
H
H
Tran
P K
PK
Vergel
S
S
Hawkins
S A
SA
Hart
C E
CE
Clowes
A W
AW
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*
D000906:Antibodies; D011993:Recombinant Fusion Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta