All-trans-retinoic acid decreases cell proliferation and increases apoptosis in an animal model of vein bypass grafting.
BACKGROUND
We have previously demonstrated a decrease in intimal hyperplasia in vein bypass grafts from animals treated with all-trans-retinoic acid (atRA). The purpose of this study was to examine the effect of atRA on proliferation and apoptosis rates in healing vein bypass grafts.


METHODS
Interposition jugular vein bypass grafts were placed in the carotid artery of 30 New Zealand white rabbits. Animals received either atRA (10 mg/kg/d) or vehicle (corn oil) for a period of 2 weeks. Animals were killed at 3, 7, or 28 days after graft placement after having received 3 doses of 5-bromo-2'-¿Deoxyuridine (BRDU, 35 Mg/KG). Animals Were Perfusion Fixed, And Vein Grafts Were Prepared For Immunohistochemistry By Using Antibodies To Brdu, Proliferating Cell Nuclear Antigen, And Bcl-XL. Apoptosis Was Measured By Using The Tunel Assay. Histologic Sections Were Analyzed By A Pathologist Blinded To The Study, And An Index Of Positively Stained Cells Was Generated For Each Layer Of The Vein Graft Wall.


RESULTS
All-trans-retinoic acid reduced the proliferation index in the neointima of vein grafts during the first week after surgery. Apoptotic rates were higher in the intima of vein grafts from animals treated with atRA, which could not be explained by changes in bcl-xl expression. No differences were noted in the media or adventitia between the groups.


CONCLUSIONS
atRA decreased cell proliferation and increased apoptosis in the intima of healing vein bypass grafts. These effects contribute to decreased intimal hyperplasia, which has been previously noted.
Division of Vascular Surgery and the Department of Pathology, Medical College of Wisconsin, Milwaukee, USA.
C D
CD
Leville
V O
VO
Osipov
J M
JM
Jean-Claude
G R
GR
Seabrook
J B
JB
Towne
R A
RA
Cambria
D000714:Anastomosis, Surgical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002339:Carotid Arteries / Q000601:surgery*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007601:Jugular Veins / Q000166:cytology / Q000601:surgery / Q000637:transplantation*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011817:Rabbits; D014182:Transplantation, Autologous; D014212:Tretinoin / Q000494:pharmacology*; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects; D014656:Vascular Surgical Procedures; D051020:bcl-X Protein
D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D014212:Tretinoin