Published online before print October 27, 2005, doi: 10.1161/01.ATV.0000193569.12490.4b
© 2006 American Heart Association, Inc.
Vascular Biology |
ß-Catenin Overexpression Augments Angiogenesis and Skeletal Muscle Regeneration Through Dual Mechanism of Vascular Endothelial Growth Factor–Mediated Endothelial Cell Proliferation and Progenitor Cell Mobilization
From the Department of Internal Medicine (K.-i.K., J.-Y.H., K.-W.P., B.-K.K., C.S.S., C.-H.K., B.-H.O., M.-M.L., Y.-B.P., H.-S.K.), Seoul National University College of Medicine, and the Cardiovascular Research Laboratory (K-i.K., H-J.C., J-Y.H., T-Y.K., K-W.P., B-K.K., C-H.K., B.-H.O., M-M.L., Y-B.P., H-S.K.) and Hormone Research Center (C.S.S.), Clinical Research Institute, Seoul National University Hospital, Korea.
Correspondence to Hyo-Soo Kim, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. E-mail hyosoo{at}snu.ac.kr
Objective— ß-Catenin plays a critical role in directing cell fate during embryogenesis, and uncontrollable activation leads to cancers, suggesting its importance in cell survival and proliferation. However, little is known regarding its role in endothelial cell (EC) and skeletal muscle proliferation and progenitor cell mobilization.
Methods and Results— ß-Catenin enhanced ECs proliferation, protected ECs from apoptosis, and increased the capillary forming capabilities, which was completely blocked by inhibition of its nuclear translocation. In addition, the increased proliferation by ß-catenin was associated with increased expression of cyclin E2. In skeletal myocytes, ß-catenin overexpression increased proliferation with cyclin D1 expression, decreased apoptosis, and induced hypertrophy. Furthermore, ß-catenin induced the expression of vascular endothelial growth factor (VEGF) in skeletal myocytes, resulting in EC proliferation. In a mouse hindlimb ischemia model, ß-catenin significantly increased recovery of blood perfusion, capillary density along with enhanced VEGF expression, and the number of proliferating ECs and myocytes. Local delivery of ß-catenin also promoted angiogenic progenitor cell mobilization and increased the number of satellite cells.
Conclusions— ß-Catenin may be an important modulator of angiogenesis and myocyte regeneration not only by directly enhancing proliferation and survival of ECs and skeletal myocytes but also by inducing VEGF expression and promoting angiogenic progenitor cell mobilization and muscle progenitor cell activation.
The role of ß-catenin in endothelial cells and myocytes has not been studied. We show that ß-catenin overexpression augments angiogenesis and skeletal muscle regeneration through not only vascular endothelial growth factor–mediated endothelial cell proliferation but also through progenitor cell mobilization or activation. These results implicate ß-catenin as an important regulator in ischemic tissue.
Key Words: ß-catenin • VEGF • angiogenesis • skeletal regeneration • progenitor cell
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