Topical application of antiangiogenic agent AGM-1470 suppresses anastomotic intimal hyperplasia after ePTFE grafting in a rabbit model.
BACKGROUND
Anastomotic intimal hyperplasia (AIH) remains an unsolved problem. Angiogenesis around the anastomosis is one of the important mechanisms accelerating AIH. In this study, we investigated the effects of an antiangiogenic agent AGM-1470 (O-[chloroacetyl-carbamoyl] fumagillol: AGM) on the thickness of AIH after expanded polytetrafluoroethylene grafting.


METHODS
Study 1: Smooth muscle cells (SMCs) were cultured to form 3-mm-side square colonies by using 4 kinds of culture medium, containing AGM at concentrations of 0, 0.1, 1.0, and 10 ng/mL. The SMC colony spreading distance in each group was measured as an index of mitogenic activity. The isolated proliferative activity of SMCs was also assessed. Study 2: Male New Zealand white rabbits underwent inlay expanded polytetrafluoroethylene grafting of the carotid arteries. They were divided in 4 groups (control, vehicle, AGM [0.5], and AGM [5]) in which no topical application, Vaseline ointment, Vaseline ointment containing 0.5 mg AGM, or Vaseline ointment containing 5 mg AGM was applied to the anastomoses, respectively. Rabbits were fed a high-cholesterol diet for 2 weeks before and 8 weeks after the operation. AIH thickness was measured and capillary formation and SMC accumulation around the anastomoses were examined with immunohistochemical staining.


RESULTS
Study 1: AGM suppressed SMC migratory activity in a cytostatic, but not cytotoxic, manner. Study 2: AGM ointment inhibited AIH in proportion to its concentration and also suppressed new capillary formation around the anastomoses and SMC accumulation in AIH.


CONCLUSIONS
Topical application of the antiangiogenic agent AGM may become an important strategy for preventing AIH.
Shigematsu
K
K
Department of Surgery, The University of Tokyo, Tokyo, Japan.
Yasuhara
H
H
Shigematsu
H
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001807:Blood Vessel Prosthesis; D002339:Carotid Arteries / Q000187:drug effects / Q000601:surgery*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents; D003510:Cyclohexanes; D006937:Hypercholesterolemia / Q000601:surgery; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D023421:Models, Animal; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009824:Ointments; D011138:Polytetrafluoroethylene; D011183:Postoperative Complications / Q000517:prevention & control; D011817:Rabbits; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D014654:Vascular Patency
D020533:Angiogenesis Inhibitors; D004396:Coloring Agents; D003510:Cyclohexanes; D009824:Ointments; D012717:Sesquiterpenes; D011138:Polytetrafluoroethylene; D000077609:O-(Chloroacetylcarbamoyl)fumagillol