Abstract 19742: Endothelial Progenitor Cells Induce Angio-Myogenesis by PPAR-δ Activation through MMP-9-mediated IGF-1 Pathway.
Background: Peroxisome proliferator-activated receptor (PPAR)-δ has been implicated in various cellular metabolisms, but the roles in vascular biology are mainly unknown. We investigated the effects of PPAR-δ activation on the paracrine networks between endothelial progenitor cells (EPCs) and endothelial cells (ECs)/skeletal muscle.
Methods: The effects of PPAR-δ activation on MMPs expression in EPCs were screened. In vitro paracrine modulation of ECs and skeletal myocytes (C2C12) by PPAR-δ activated EPCs was assessed using conditioned medium (CM) from EPCs. In vivo effects of PPAR-δ activation were determined using murine hindlimb ischemia and skin punch wound models.
Results: GW501516, a PPAR-δ agonist treatment specifically increased mRNA and protein expression of MMP-9 in EPCs. ChIP and promoter assays revealed this increase occurred through direct transcriptional activation. When CM from GW501516 treated EPCs was incubated with insulin-like growth factor binding protein (IGFBP)-3, it degraded IGFBP-3 in a MMP-9 dependent manner. Treatment of the CM phosphorylated IGF-1 receptor (R) in human umbilical vein ECs and C2C12, resulting in the enhancement of numbers and functions of them. These effects were reversed by MMP inhibitor and IGF-1R neutralizing antibody pretreatment. Systemic administration of GW501516 in mice increased MMP-9 expression in EPCs, and augmented IGFBP-3 degradation in serum. In a mouse hindlimb ischemia model, systemic administration of GW501516 induced IGF-1R phosphorylation in ECs and skeletal muscle, leading to augmented angiogenesis and skeletal muscle regeneration. It also enhanced wound healing with increased angiogenesis in a mouse skin punch wound model. These in vivo effects by GW501516 were abolished in MMP-9 KO mice.
Conclusions: PPAR-δ is a crucial modulator of angio-myogenesis via the paracrine effects of EPCs, and its agonist is a good candidate as a therapeutic drug for patients with peripheral vascular diseases.
- Endothelial progenitor cell
- Muscle, skeletal
- Regenerative medicine stem cells
- Progenitor cell
- © 2010 by American Heart Association, Inc.