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

• Published in: Circulation Journal 2013, Vol.77(4), pp.1053-1062
• Main Authors: Aburakawa, Yoko, Kawabe, Jun-ichi, Okada, Motoi, Yamauchi, Atsushi, Asanome, Akira, Kabara, Maki, Matsuki, Motoki, Takehara, Naofumi, Nakagawa, Naoki, Okumura, Shunsuke, Minami, Yoshinori, Mizukami, Yusuke, Yuhki, Koh-ichi, Ushikubi, Fumitaka, Hasebe, Naoyuki
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Bone Marrow Transplantation; Cell Adhesion; Disease Models, Animal; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial progenitor cells; Epoprostenol - genetics; Epoprostenol - metabolism; Hind limb ischemia; Hindlimb - blood supply; Hindlimb - metabolism; Hindlimb - pathology; Ischemia - genetics; Ischemia - metabolism; Ischemia - therapy; Male; Mice; Mice, Knockout; Microcirculation; Neovascularization, Physiologic; Pericytes - metabolism; Pericytes - pathology; Prostacyclin; Receptors, Prostaglandin - genetics; Receptors, Prostaglandin - metabolism; Stem Cells - metabolism; Stem Cells - pathology
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-12-0897

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)