oa Soluble CD40 Ligand Stimulates the Pro-Angiogenic Function of Early Endothelial Progenitor Cells by Increasing Matrix Metalloproteinase 9 Release via the p38 Mitogen Activated Protein Kinase Pathway

Endothelial progenitor cells (EPCs) have recently been regarded as potential therapeutic targets in vascular repair. The effects of EPCs are related to their incorporation at sites of vascular lesions and to their release of various angiogenic factors. It has been shown that soluble CD40 ligand (sCD40L) levels are elevated in patients suffering from cardiovascular disease, which may influence the function of EPCs. We have identified the expression of the inflammatory receptor CD40 on early EPCs and aimed to study the effect of its ligand, sCD40L, on the function of early EPCs in angiogenesis.

Early EPCs derived from cultured peripheral blood mononuclear cells express CD40, and their stimulation with sCD40L increased the binding of the tumor necrosis factor receptor-associated factors, TRAF1, TRAF2, but not TRAF3, to CD40, indicating the existence of a functional signaling pathway via the CD40L/CD40 axis in early EPCs. Early EPCs alone do not display any tube formation potential on matrigel, but following stimulation with sCD40L, they significantly increased the angiogenic potential of cultured human umbilical vein endothelial cells (HUVECs), as determined by wound healing assay. Stimulation of early EPCs with sCD40L increased, in a concentration-dependent manner, the release of matrix metalloproteinase 9 (MMP-9) via the p38 mitogen activated protein kinase (MAPK) pathway. Inhibition of p38 MAPK, by SB203580, in sCD40L-treated early EPCs, reversed their release of MMP-9 and their pro-angiogenic effect on HUVECs.

We have shown that sCD40L increases the pro-angiogenic function of early EPCs on cultured HUVECs by inducing a significant increase in MMP-9 release via the p38 MAPK signaling pathway.