Id1 gene transfer confers angiogenic property on fully differentiated endothelial cells and contributes to therapeutic angiogenesis.
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.


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.
Nishiyama
Koichi
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. nkanako@gpo.kumamoto-u.ac.jp
Takaji
Kentaro
K
Kataoka
Keiichiro
K
Kurihara
Yukiko
Y
Yoshimura
Michihiro
M
Kato
Atsushi
A
Ogawa
Hisao
H
Kurihara
Hiroki
H
D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002478:Cells, Cultured; D017931:DNA Primers; D004622:Embryo, Mammalian; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus; D014471:Umbilical Veins
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D017931:DNA Primers; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1