β-Catenin Overexpression Augments Angiogenesis and Skeletal Muscle Regeneration Through Dual Mechanism of Vascular Endothelial Growth Factor–Mediated Endothelial Cell Proliferation and Progenitor Cell Mobilization

Abstract

Objective-␤-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-␤-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 ␤-catenin was associated with increased expression of cyclin E2. In skeletal myocytes, ␤-catenin overexpression increased proliferation with cyclin D1 expression, decreased apoptosis, and induced hypertrophy. Furthermore, ␤-catenin induced the expression of vascular endothelial growth factor (VEGF) in skeletal myocytes, resulting in EC proliferation. In a mouse hindlimb ischemia model, ␤-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 ␤-catenin also promoted angiogenic progenitor cell mobilization and increased the number of satellite cells. Key Words: ␤-catenin Ⅲ VEGF Ⅲ angiogenesis Ⅲ skeletal regeneration Ⅲ progenitor cell ␤ -Catenin is an intracellular protein known to play dual roles in cells. In addition to its structural role in maintaining tissue architecture and cell polarity at adherens junctions, cytoplasmic ␤-catenin also translocates into the nucleus where it forms a complex with transcription factors of the Tcf/Lef family and activates the expression of specific genes involved in cell proliferation and survival. 1,2 Although the critical role of ␤-catenin on the proliferative and migratory responses of cells during embryogenesis and in neoplastic disease have been well described previously, relatively little is known about the role of ␤-catenin on the endothelial cell (EC) in normal, controlled cell proliferation and migration. 3,4 Recent data suggest that Wnt/␤-catenin signaling may play a key role in vascular biology. For example, transfection of Wnt-1-expressing vector was shown to stimulate EC proliferation with ␤-catenin accumulation, which implies that Wnt proteins may regulate signal transduction in ECs via ␤-catenin. 5 Furthermore, ␤-catenin was also identified in the cytoplasm of ECs of newly formed vessels around the area of infarction. 6 In a recent study, 7 the human vascular endothelial growth factor (VEGF) gene promoter has been reported to contain binding sites for ␤-catenin/Tcf, and the transfection of ␤-catenin to normal colon epithelial cells significantly increased VEGF expression. In addition, the Wnt pathway is also reported to play an important role in muscle regeneration. 8 However, the downstream target genes and the exact mechanisms of the Wnt/␤-catenin signaling pathway in ECs and skeletal muscle cells have not been clarified. Therefore, the aim of the presen...

Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration

“…Taken together, these results suggest that nuclear localisation of Act-β-Cat results in the proliferation of satellite cells and that its distribution outside of the nucleus is indicative of cells that are mitotically inactive. This work is in agreement with the finding that the forced overexpression of β-catenin during ischaemia-induced muscle damage leads to increased myoblast proliferation and enhanced muscle repair (Kim et al, 2006).…”

Muscle Satellite Cells and Endothelial Cells: Close Neighbors and Privileged Partners

“…Exercise-induced VEGF up-regulation in muscle cells operate physiological angiogenesis (Egginton et al, 2001;Ameln et al, 2005). Myoblasts manipulated to produce VEGF specifically promote HUVEC proliferation (Kim et al, 2006) and induce pronounced localized angiogenesis in their immediate vicinity after im transplantation (Springer et al, 2003). A steep gradient of VEGF concentration emanating from the implantation site into neighboring host muscle tissue has been repeatedly predicted, but was not previously documented by immunolocalization (Springer et al, 2003;Mac Gabhann et al, 2006).…”

Regulation of myogenic stem cell behaviour by vessel cells: The "ménage à trois" of satellite cells, periendothelial cells and endothelial cells

“…31 Other factors has been shown to be involved in the regulation of angiogenesis in skeletal muscle, such as β-catenin, which overexpression induces both angiogenesis (through Endothelial Cell (EC) proliferation) and muscle regeneration (increases VEGF expression in myogenic cells). 32 Fibroblast Growth Factor (FGF) s seem also involved: myogenic cells express bFGF that leads to angiogenesis in a paracrine fashion to help muscle regeneration in ischemic limb, 33 while introducing FGF2 or FGF6 transgenes into muscle enhances both the number of CD31 + structures, i.e., vessels, and muscle repair. 34 Finally, Nerve Growth Factor (NGF) has been shown to enhance angiogenesis and arteriogenesis after ischemia in vivo while it protects ECs and myofibres from apoptosis in vitro.…”