Probucol and antioxidant vitamins rescue ischemia-induced neovascularization in mice exposed to cigarette smoke: Potential role of endothelial progenitor cells

• Published in: Atherosclerosis 2010-02, Vol.208 (2), p.342-349
• Main Authors: Turgeon, Julie, Dussault, Sylvie, Haddad, Paola, Groleau, Jessika, Ménard, Catherine, Michaud, Sophie-Élise, Maingrette, Fritz, Rivard, Alain
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antioxidants; Antioxidants - metabolism; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cardiovascular; Cells, Cultured; Cigarette smoking; Endothelial Cells - cytology; Endothelial progenitor cells; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Ischemia - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Nicotiana - adverse effects; Probucol - pharmacology; Reactive Oxygen Species; Smoke; Stem Cells - cytology; Vertebrates: cardiovascular system; Vitamins - metabolism
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2009.08.007

Abstract 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. Methods and 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.