Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: impairment of the HIF-1alpha/VEGF pathway.
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-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in hypoxic conditions. Administration of an adenoviral vector encoding for HIF-1alpha/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-1alpha in hypoxic conditions.
Michaud
Sophie-Elise
SE
Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, 1560 Sherbrooke Est, Suite Y-3605, Montreal, Quebec, H2L 4M1, Canada.
Ménard
Catherine
C
Guy
Louis-Georges
LG
Gennaro
Giuseppa
G
Rivard
Alain
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development; D005822:Genetic Vectors; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines / Q000037:antagonists & inhibitors*; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors