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Inhibition of hypoxia‐induced angiogenesis by cigarette smoke exposure: impairment of the HIF‐lalpha/VEGF pathway
Author(s) -
Michaud Sophie-Élise,
Ménard Catherine,
Guy Louis-Georges,
Gennaro Giuseppa,
Rivard Alain
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0172fje
Subject(s) - angiogenesis , vascular endothelial growth factor , neovascularization , hypoxia (environmental) , in vivo , ischemia , medicine , hif1a , pharmacology , endocrinology , immunology , chemistry , biology , vegf receptors , microbiology and biotechnology , organic chemistry , oxygen
Smoking is a major risk factor for atherosclerotic diseases. However, the impact of cigarette smoke exposure on neovascularization that develops in response to tissue ischemia is unknown. Here we demonstrate that cigarette smoke extracts inhibit hypoxia‐induced in vitro angiogenesis (matrigel assay) in human umbilical vascular endothelial cells. In vivo , mice exposed to cigarette smoke (MES) were shown to have a significant impairment of angiogenesis following surgically induced hindlimb ischemia. The reduced angiogenic response in MES was documented by Laser Doppler flow perfusion studies and capillary density analyses in ischemic hindlimbs. Inhibition of angiogenesis by cigarette smoke in vitro and in vivo was associated with a reduced expression of hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) in hypoxic conditions. Administration of an adenoviral vector encoding for HIF‐1α/VP16, a hybrid transcription factor that is stable in hypoxic and normoxic conditions, restored VEGF expression and completely reversed the cigarette smoke inhibition of angiogenesis in hypoxic conditions. Taken together, these results suggest that cigarette smoke exposure impairs angiogenesis by inhibiting VEGF through decreased expression of HIF‐1α in hypoxic conditions.