A role for the aryl hydrocarbon receptor in regulation of ischemia-induced angiogenesis.
OBJECTIVE
The aryl hydrocarbon receptor (AHR) is a transcription factor that binds to DNA as a heterodimer with the AHR nuclear translocator (ARNT) after interaction with ligands such as polycyclic and halogenated aromatic hydrocarbons found in tobacco smoke and the environment. We have investigated the interaction between AHR and hypoxia signaling pathways in regulation of angiogenesis with the use of a surgical model of ischemia.


RESULTS
Ischemia was induced by femoral artery occlusion in wild-type and AHR-null mice. Ischemia-induced angiogenesis was markedly enhanced in AHR-null mice compared with that in wild-type animals. Ischemia-induced upregulation of the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and ARNT as well as that of target genes for these transcription factors, such as that for vascular endothelial growth factor (VEGF), were also enhanced in AHR-null mice. Furthermore, the DNA binding activity of the HIF-1alpha-ARNT complex as well as the association of HIF-1alpha and ARNT with the VEGF gene promoter were increased by ischemia to a greater extent in AHR-null mice than in wild-type animals.


CONCLUSIONS
Ablation of AHR resulted in enhancement of ischemia-induced angiogenesis. This effect was likely attributable in part to the associated enhancement of ischemia-induced VEGF expression, which in turn may be caused by an increased abundance and activity of the HIF-1alpha-ARNT heterodimer.
Ichihara
Sahoko
S
Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu 514-8507, Japan. saho@gene.mie-u.ac.jp
Yamada
Yoshiji
Y
Ichihara
Gaku
G
Nakajima
Tamie
T
Li
Ping
P
Kondo
Takahisa
T
Gonzalez
Frank J
FJ
Murohara
Toyoaki
T
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001783:Blood Flow Velocity; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D002273:Carcinogens / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000601:surgery; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012039:Regional Blood Flow; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042501:Angiogenic Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D002273:Carcinogens; D004247:DNA; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D020797:Receptor, Platelet-Derived Growth Factor beta; D018336:Receptors, Aryl Hydrocarbon; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; C484722:Ahr protein, mouse; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse