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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2535.)
© 2005 American Heart Association, Inc.

Vascular Biology

Therapeutic Angiogenesis With Intramuscular Injection of Low-Dose Recombinant Granulocyte-Colony Stimulating Factor

Mejeong Lee; Mika Aoki; Takahisa Kondo; Koichi Kobayashi; Kenji Okumura; Kimihiro Komori; Toyoaki Murohara

From the Departments of Cardiology and Vascular Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Correspondence to Toyoaki Murohara, MD, PhD, FAHA, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550 Japan. E-mail murohara{at}med.nagoya-u.ac.jp

Objective— In vivo administration of granulocyte colony-stimulating factor (G-CSF) has been shown to facilitate regeneration of cardiovascular tissues. However, G-CSF causes marked leukocytosis that potentially induces adverse cardiovascular events. Earlier studies showed that G-CSF had direct stimulatory actions on mature endothelial cells, resulting in promotion of angiogenesis. We thus examined whether low doses of recombinant human G-CSF (rhG-CSF) locally injected into ischemic tissues would stimulate angiogenesis without inducing severe leukocytosis.

Methods and Results— Reverse-transcription polymerase chain reaction (PCR) revealed expression of G-CSF receptor in human umbilical vein endothelial cells (HUVECs). rhG-CSF (100 ng/mL) enhanced migration and tube formation but not proliferation of HUVECs in vitro. We then examined the effects of rhG-CSF on angiogenesis in a rat model of hindlimb ischemia. Nude rats received in their ischemic skeletal muscles either rhG-CSF (2, 10, 20 µg/kg per day) or saline (control) for 6 days. Laser Doppler blood flowmetry (LDBF) revealed an augmented ischemic/normal limb LDBF ratio and an increased capillary density in the rhG-CSF–treated groups compared with the control at days 14, 21, and 28 (P<0.05). These doses of rhG-CSF induced only mild leukocytosis (1.4-fold increases versus baseline).

Conclusions— rhG-CSF promoted endothelial migration and tube formation in vitro. Local injection of low doses rhG-CSF effectively augmented ischemia-induced angiogenesis in vivo. This treatment regimen of low-dose rhG-CSF may become a new and safe modality for therapeutic angiogenesis.

G-CSF receptor was expressed in human umbilical vein endothelial cells (HUVECs). rhG-CSF (100 ng/mL) enhanced migration and tube formation but not proliferation of HUVECs. Moreover, local injection of low doses rhG-CSF augmented ischemia-induced angiogenesis in vivo. This treatment regimen of low-dose rhG-CSF may become a new and safe modality for therapeutic angiogenesis.

Key Words: angiogenesis • endothelial cell • ischemia • rhG-CSF

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