Angiopoietin-related growth factor enhances blood flow via activation of the ERK1/2-eNOS-NO pathway in a mouse hind-limb ischemia model

Takashi Urano, Yasuhiro Ito, Masaki Akao, Tomohiro Sawa, Keishi Miyata, Mitsuhisa Tabata, Tohru Morisada, Tai Hato, Masato Yano, Tsuyoshi Kadomatsu, Kunio Yasunaga, Rei Shibata, Toyoaki Murohara, Takaaki Akaike, Hidenobu Tanihara, Toshio Suda, Yuichi Oike

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

OBJECTIVE - Transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis, suggesting that AGF may be a useful drug target in ischemic disease. Our goal was to determine whether AGF enhances blood flow in a mouse hind-limb ischemia model and to define molecular mechanisms underlying AGF signaling in endothelial cells. METHODS AND RESULTS - Intramuscular injection of adenovirus harboring AGF into the ischemic limb increased AGF production, which increased blood flow through induction of angiogenesis and arteriogenesis, thereby reducing the necessity for limb amputation. In vitro analysis showed that exposing human umbilical venous endothelial cells to AGF increased nitric oxide (NO) production through activation of an ERK1/2-endothelial NO synthetase (eNOS) signaling pathway. AGF-stimulated eNOS phosphorylation, NO production, and endothelial cell migration were all abolished by specific MEK1/2 inhibitors. Moreover, AGF did not restore blood flow to ischemic hind-limbs of either mice receiving NOS inhibitor L-NAME or eNOS knockout mice. CONCLUSION - Activation of an ERK1/2-eNOS-NO pathway is a crucial signaling mechanism by which AGF increases blood flow through induction of angiogenesis and arteriogenesis. Further investigation of the regulation underlying AGF signaling pathway may contribute to develop a new clinical strategy for ischemic vascular diseases.

Original languageEnglish
Pages (from-to)827-834
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number5
DOIs
Publication statusPublished - 2008 May 1

    Fingerprint

Keywords

  • Angiopoietin-related growth factor
  • Endothelial nitric oxide synthetase
  • Extracellular signal-regulated kinase 1/2
  • Nitric oxide
  • Therapeutic angiogenesis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Urano, T., Ito, Y., Akao, M., Sawa, T., Miyata, K., Tabata, M., Morisada, T., Hato, T., Yano, M., Kadomatsu, T., Yasunaga, K., Shibata, R., Murohara, T., Akaike, T., Tanihara, H., Suda, T., & Oike, Y. (2008). Angiopoietin-related growth factor enhances blood flow via activation of the ERK1/2-eNOS-NO pathway in a mouse hind-limb ischemia model. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(5), 827-834. https://doi.org/10.1161/ATVBAHA.107.149674