title: Soluble CD40 ligand stimulates the pro-angiogenic function of peripheral blood angiogenic outgrowth cells via increased release of matrix metalloproteinase-9.
abstract: The role of endothelial progenitor cells in vascular repair is related to their incorporation at sites of vascular lesions, differentiation into endothelial cells, and release of various angiogenic factors specifically by a subset of early outgrowth endothelial progenitor cells (EOCs). It has been shown that patients suffering from cardiovascular disease exhibit increased levels of circulating and soluble CD40 ligand (sCD40L), which may influence the function of EOCs. We have previously shown that the inflammatory receptor CD40 is expressed on EOCs and its ligation with sCD40L impairs the anti-platelet function of EOCs. In the present study, we aimed at investigating the effect of sCD40L on the function of EOCs in endothelial repair. Human peripheral blood mononuclear cell-derived EOCs express CD40 and its adaptor proteins, the tumor necrosis factor receptor-associated factors; TRAF1, TRAF2 and TRAF3. Stimulation of EOCs with sCD40L increased the expression of TRAF1, binding of TRAF2 to CD40 and phosphorylation of p38 mitogen activated protein kinase (MAPK). In an in vitro wound healing assay, stimulation of EOCs with sCD40L increased the release of matrix metalloproteinase 9 (MMP-9) in a concentration-dependent manner and significantly enhanced the angiogenic potential of cultured human umbilical vein endothelial cells (HUVECs). Inhibition of p38 MAPK reversed sCD40L-induced MMP-9 release by EOCs, whereas inhibition of MMP-9 reversed their pro-angiogenic effect on HUVECs. This study reveals the existence of a CD40L/CD40/TRAF axis in EOCs and shows that sCD40L increases the pro-angiogenic function of EOCs on cultured HUVECs by inducing a significant increase in MMP-9 release via, at least, the p38 MAPK signaling pathway.
authors.affiliation: Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Lara
authors.initials: L
authors.lastname: Bou Khzam
authors.affiliation: Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Rahma
authors.initials: R
authors.lastname: Boulahya
authors.affiliation: Qatar Cardiovascular Research Center, Qatar Foundation-Education City, Doha, Qatar.
authors.forename: Haissam
authors.initials: H
authors.lastname: Abou-Saleh
authors.affiliation: Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hachem
authors.affiliation: Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Younes
authors.initials: Y
authors.lastname: Zaid
authors.affiliation: Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montréal, Québec, Canada ; Université de Montréal, Department of Medicine, Montréal, Québec, Canada.
authors.forename: Yahye
authors.initials: Y
authors.lastname: Merhi
mesh_terms: D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D023201:CD40 Ligand; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9