Concomitant blockade of platelet-derived growth factor receptors alpha and beta induces intimal atrophy in baboon PTFE grafts.
OBJECTIVE
Although current treatments for restenosis attempt to prevent the development of intimal hyperplasia, an alternative strategy is to induce intimal atrophy after restenosis has developed. Because platelet-derived growth factor (PDGF) is a smooth muscle cell growth and survival factor, we tested the hypothesis that complete blockade of PDGF by using antibodies against PDGF receptors alpha and beta would cause intimal atrophy in a baboon vascular graft model.


METHODS
We administered chimeric antibodies against PDGF receptor alpha or PDGF receptor beta, either separately or together, to baboons with bilateral prosthetic aortoiliac grafts, the intimas of which had reached maximal size before treatment was begun. High blood flow, which we have previously shown to cause intimal atrophy, was induced through one graft to serve as a positive control. After 2 weeks, the intima lining the grafts was assessed for cross-sectional area, cell proliferation, and apoptosis by standard morphologic and immunohistochemical techniques.


RESULTS
Blocking both PDGF receptors simultaneously reduced the cross-sectional area of the normal-flow graft intima by 44% (P <.05 vs control), whereas treatment with the individual antibodies did not significantly alter intimal area. Blockade of both receptors also inhibited smooth muscle cell proliferation by 66% (P <.05 vs control), whereas neither antibody alone altered proliferation. In contrast, all treatments increased smooth muscle cell apoptosis threefold to fivefold.


CONCLUSIONS
These data suggest that simultaneous inhibition of cell proliferation and stimulation of cell death by the administration of antibodies to both PDGF receptor alpha and receptor beta is required for intimal atrophy in this baboon graft model. In addition, these data provide an in vivo model for the pharmacologic induction of intimal atrophy and introduce a novel clinical approach to treat intimal hyperplasia. Clinical relevance This study introduces the concept of pharmacologic induction of intimal atrophy. Intimal hyperplasia plagues all forms of arterial reconstruction. Currently, the only effective treatment of these restenotic lesions is balloon angioplasty or operative revision. An alternative approach to patients with clinically significant intimal hyperplasia might be to stimulate intimal regression by modulating growth and survival factors required for intimal maintenance. Although PDGF is known to be critical in intimal formation, the results of this study suggest that PDGF is also critical for intimal maintenance. Inhibition of the PDGF system may prove to be a clinically applicable approach for inducing intimal atrophy.
Englesbe
Michael J
MJ
Department of Surgery, University of Washington Medical Center, Seattle, WA 98195, USA.
Hawkins
Suzanne M
SM
Hsieh
Patrick C H
PC
Daum
Günter
G
Kenagy
Richard D
RD
Clowes
Alexander W
AW
D000818:Animals; D001284:Atrophy; D001807:Blood Vessel Prosthesis; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D008297:Male; D010215:Papio; D011138:Polytetrafluoroethylene; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D017539:Tunica Intima / Q000473:pathology*
D011138:Polytetrafluoroethylene; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta