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

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概要

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• 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.

著者

• Ushikubi Fumitaka

  Department Of Pharmacology Asahikawa Medical College

• Takehara Naofumi

  Department Of Cardiology Asahikawa Medical College

• Aburakawa Yoko

  Division of Neurology, Department of Internal Medicine, Asahikawa Medical College

• Kawabe Junichi

  Department Of 1st Internal Medicine Asahikawa Medical College

• Yuhki Kohichi

  Department of Pharmacology, Asahikawa Medical College

• Yuhki Koh-ichi

  Department Of Cardiovascular Medicine Asahikawa Medical College

• Mizukami Yusuke

  Division Of Gastroenterology And Hematology/oncology Department Of Medicine Asahikawa Medical Colleg

• Kawabe Jun-ichi

  Department Of Cardiology Asahikawa Medical College

• Nakagawa Naoki

  Division Of Cardiology Nephrology Pulmonology And Neurology Department Of Internal Medicine Asahikawa Medical University

• Matsuki Motoki

  Division Of Cardiology Nephrology Pulmonology And Neurology Department Of Internal Medicine Asahikawa Medical University

• Kabara Maki

  Division Of Cardiology Nephrology Pulmonology And Neurology Department Of Internal Medicine Asahikawa Medical University

• Kawabe Jun-ichi

  Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University

• Hasebe Naoyuki

  Department of Cardiolog, Asahikawa Medical University

• Yamauchi Atsushi

  Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University

• Takehara Naofumi

  Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University

• Okada Motoi

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Asanome Akira

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Okumura Shunsuke

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Minami Yoshinori

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Matsuki Motoki

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Yamauchi Atsushi

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Aburakawa Yoko

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

• Yuhki Koh-ichi

  Department of Pharmacology, Asahikawa Medical University

• 油川 陽子

  Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University

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