Probucol and antioxidant vitamins rescue ischemia-induced neovascularization in mice exposed to cigarette smoke: potential role of endothelial progenitor cells.
OBJECTIVE
Cigarette smoking is associated with impaired neovascularization in response to ischemia. Potential mechanisms include increased generation of reactive oxygen species (ROS) and a reduction in the function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that antioxidant therapies could stimulate EPC function and improve ischemia-induced neovascularization following cigarette smoke exposure.


RESULTS
C57Bl/6 mice exposed to cigarette smoke (MES) were fed a normal diet (controls) or a diet supplemented with probucol (0.5%) or a combination of vitamin C (25 g/l in drinking water) and vitamin E (0.1% in normal chow). After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Exposure to cigarette smoke was associated with a significant reduction of blood flow recuperation and vessel density in ischemic muscles. However, a complete rescue of neovascularization was demonstrated in MES treated with probucol or antioxidant vitamins. We found that antioxidant therapy in MES is associated with a significant reduction of oxidative stress levels both in the plasma and in ischemic muscles. Moreover, EPCs exposed to cigarette smoke extracts in vitro showed a significant impairment of their angiogenic activities (migration, adhesion, homing into ischemic tissues) that was completely rescued by probucol and antioxidant vitamins.


CONCLUSIONS
Probucol and antioxidant vitamins rescue cigarette smoke-dependent impairment of ischemia-induced neovascularization. The mechanisms involve beneficial effects on oxidative stress levels in ischemic tissues together with an improvement of EPC functional activities. Antioxidant therapy could constitute a novel therapeutic strategy to promote vessel growth and reduce tissue ischemia in atherosclerotic diseases.
Turgeon
Julie
J
Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2L 4M1, Canada.
Dussault
Sylvie
S
Haddad
Paola
P
Groleau
Jessika
J
Ménard
Catherine
C
Michaud
Sophie-Elise
SE
Maingrette
Fritz
F
Rivard
Alain
A
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D007511:Ischemia / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D011341:Probucol / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D012906:Smoke; D013234:Stem Cells / Q000166:cytology*; D014026:Nicotiana / Q000009:adverse effects; D014815:Vitamins / Q000378:metabolism*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D012906:Smoke; D014815:Vitamins; D011341:Probucol