Prostacyclin Stimulated Integrin-Dependent Angiogenic Effects of Endothelial Progenitor Cells and Mediated Potent Circulation Recovery in Ischemic Hind Limb Model

Yoko Aburakawa; Jun-ichi Kawabe; Motoi Okada; Atsushi Yamauchi; Akira Asanome; Maki Kabara; Motoki Matsuki; Naofumi Takehara; Naoki Nakagawa; Shunsuke Okumura; Yoshinori Minami; Yusuke Mizukami; Koh-ichi Yuhki; Fumitaka Ushikubi; Naoyuki Hasebe

doi:10.1253/circj.CJ-12-0897

Regenerative Medicine

Prostacyclin Stimulated Integrin-Dependent Angiogenic Effects of Endothelial Progenitor Cells and Mediated Potent Circulation Recovery in Ischemic Hind Limb Model

Yoko Aburakawa, Jun-ichi Kawabe, Motoi Okada, Atsushi Yamauchi, Akira Asanome, Maki Kabara, Motoki Matsuki, Naofumi Takehara, Naoki Nakagawa, Shunsuke Okumura, Yoshinori Minami, Yusuke Mizukami, Koh-ichi Yuhki, Fumitaka Ushikubi, Naoyuki Hasebe

Author information

Yoko Aburakawa
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Jun-ichi Kawabe
Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University
Motoi Okada
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Atsushi Yamauchi
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Akira Asanome
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Maki Kabara
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Motoki Matsuki
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Naofumi Takehara
Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University
Naoki Nakagawa
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Shunsuke Okumura
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Yoshinori Minami
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University
Yusuke Mizukami
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
Koh-ichi Yuhki
Department of Pharmacology, Asahikawa Medical University
Fumitaka Ushikubi
Department of Pharmacology, Asahikawa Medical University
Naoyuki Hasebe
Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University
Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

Keywords: Angiogenesis, Endothelial progenitor cells, Hind limb ischemia, Prostacyclin

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Supplementary material

2013 Volume 77 Issue 4 Pages 1053-1062

DOI https://doi.org/10.1253/circj.CJ-12-0897

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Abstract

Background: Prostacyclin (PGI₂) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI₂ in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI₂ in EPC-mediated angiogenesis using BM-specific IP deletion mice. Methods and Results: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IP-deleted BM (WT/BM(IP^–/–). Recovery of blood flow (RBF) in WT/BM(IP^–/–) was impaired for 28 days after HLI, whereas RBF in IP^–/–/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP^–/–) was completely recovered by intramuscular injection of WT EPCs but not IP^–/– EPCs. The impaired effects of IP^–/– EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP^–/–EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin β1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects. Conclusions: PGI₂ may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects. (Circ J 2013; 77: 1053–1062)

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