Prostacyclin Stimulated Integrin-Dependent Angiogenic Effects of Endothelial Progenitor Cells and Mediated Potent Circulation Recovery in Ischemic Hind Limb Model
Prostacyclin Stimulated Integrin-Dependent Angiogenic Effects of Endothelial Progenitor Cells and Mediated Potent Circulation Recovery in Ischemic Hind Limb Model
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DOI：
10.1253/circj.cj-12-0897
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发表时间：
2013-04-01
影响因子：
3.3
通讯作者：
Hasebe, Naoyuki
中科院分区：
文献类型：
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作者：
Aburakawa, Yoko;Kawabe, Jun-ichi;Hasebe, Naoyuki
背景：前列环素（PGI(2)）促进血管生成，特别是与骨髓（BM）来源的内皮祖细胞（EPCs）合作。然而，PGI2在内皮细胞介导的血管生成中的作用机制尚不清楚。本研究的目的是利用脑卒中特异性IP缺失小鼠阐明PGI2在epc介导的血管生成中的作用。方法与结果：野生型（WT）小鼠移植IF-deleted BM(WT/BM（IP-/-）后肢体缺血（HLI）。在HLI后28天，WT/BM（IP-/-）的血流恢复（RBF）受损，而与WT/BM（WT）相比，IP-/-/BM（WT）的血流恢复（RBF）减弱长达7天。肌内注射WT -/- EPCs后，WT/BM（IP-/-）损伤的RBF完全恢复，而IP-/- EPCs则不能。IP-/- epcs的损伤作用与缺血肌肉中毛细血管和小动脉形成减少一致。体外主动脉环实验显示，内皮祖细胞作为周细胞在血管周围部位的积累/粘附促进了微血管的形成。整合素表达降低的IP-/- epcs抑制了血管生成细胞因子的产生、对新血管的粘附以及它们的血管生成作用。小干扰RNA （siRNA）介导的WT EPCs中整合素β 1的下调减弱了其对微血管的粘附及其在体内和体外的血管生成作用。结论：除了旁分泌作用外，PGI2还可能通过整合素使内皮祖细胞粘附到新生血管的血管周围部位，从而诱导HLI持续的血管生成作用。（Circ J 2013; 77: 1053-1062）
Background: Prostacyclin (PGI(2)) 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 IF-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 beta 1 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)