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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1297.)
© 2007 American Heart Association, Inc.

Vascular Biology

A Role for the Aryl Hydrocarbon Receptor in Regulation of Ischemia-Induced Angiogenesis

Sahoko Ichihara; Yoshiji Yamada; Gaku Ichihara; Tamie Nakajima; Ping Li; Takahisa Kondo; Frank J. Gonzalez; Toyoaki Murohara

From the Department of Human Functional Genomics (S.I., Y.Y.), Life Science Research Center, Mie University, Tsu, Japan; Social Life Science (S.I., G.I., T.N.) and Department of Cardiology (P.L., T.K., T.M.), Nagoya University Graduate School of Medicine, Nagoya, Japan; and the Laboratory of Metabolism (F.J.G.), National Cancer Institute, NIH, Bethesda, Md.

Correspondence to Sahoko Ichihara, MD, PhD, Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu 514-8507, Japan. E-mail saho{at}gene.mie-u.ac.jp

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.

Methods and 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–1 (HIF-1) 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-1–ARNT complex as well as the association of HIF-1 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-1–ARNT heterodimer.

Ischemia-induced angiogenesis was markedly enhanced in aryl hydrocarbon receptor (AHR)-null mice. This effect may be attributable to an increased association of hypoxia-inducible factor-1 with the AHR nuclear translocator and a consequent increased production of vascular endothelial growth factor in AHR-null mice.

Key Words: angiogenesis • hypoxia • ischemia • peripheral vascular disease • smoking

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