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(Circulation. 2005;112:2840-2850.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Id1 Gene Transfer Confers Angiogenic Property on Fully Differentiated Endothelial Cells and Contributes to Therapeutic Angiogenesis

Koichi Nishiyama, MD; Kentaro Takaji, MD; Keiichiro Kataoka, MD; Yukiko Kurihara, MD, PhD; Michihiro Yoshimura, MD; Atsushi Kato, PhD; Hisao Ogawa, MD; Hiroki Kurihara, MD, PhD

From the Departments of Cardiovascular Medicine (K.N., K.K., M.Y., H.O.) and Cardiovascular Surgery (K.T.), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Physiological Chemistry and Metabolism, Division of Biochemistry and Molecular Biology (Y.K., H.K.), and Department of Developmental and Medical Technology (Sankyo) (K.N.), University of Tokyo Graduate School of Medicine, Tokyo, Japan; and Department of Viral Infection and Vaccine Control, National Institute for Infectious Diseases (A.K.), Tokyo, Japan.

Correspondence to Koichi Nishiyama, MD, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan, or Department of Developmental and Medical Technology (Sankyo), University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail nkanako{at}gpo.kumamoto-u.ac.jp or nkanako@bio.m.u-tokyo.ac.jp

Received October 26, 2004; revision received June 21, 2005; accepted August 8, 2005.

Background— Transplantation of endothelial progenitor cells has been proposed as a potential strategy for therapeutic revascularization. However, the limited endogenous cell pool and the related technical difficulties constitute clinically important disadvantages to autologous transplantation. In this study we investigated whether fully differentiated endothelial cells (ECs) modified with gene transfer of Id1, a helix-loop-helix transcription factor involved in angiogenesis, have the potential to contribute to therapeutic angiogenesis.

Methods and Results— The Id1 gene was transferred into human umbilical vein ECs (HUVECs) via a Sendai virus vector. Id1 stimulated migration, proliferation, and capillary-like tube/cord formation of HUVECs. In addition, Id1 reduced serum deprivation–induced HUVEC apoptosis, as shown by FACS analysis with annexin V and TUNEL staining. Transplantation of Id1-overexpressing HUVECs accelerated recovery of blood flow as evaluated by laser-Doppler perfusion imaging, increased capillary density, and improved the rate of limb salvage compared with the transplantation of control HUVECs. Histochemical analysis revealed that the regenerated vascular networks of limbs transplanted with Id1-overexpressing HUVECs contained numerous HUVECs, some of which were in a proliferative state. Untransfected HUVECs were also incorporated with Id1-transfected HUVECs, suggesting the noncell autonomous effect of Id1. Finally, angiopoietin-1 was upregulated in Id1-overexpressing HUVECs and functionally contributed to the in vitro angiogenic effect of Id1.

Conclusions— Id1 gene transfer conferred HUVECs with an angiogenic property, contributing to neovascularization after transplantation into ischemic lesions. Transplantation of Id1-overexpressing mature ECs may serve as a novel and useful strategy for therapeutic angiogenesis.

Key Words: endothelial cells • genes • therapeutic angiogenesis

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