Submitted August 13, 2008
Accepted February 27, 2009
Inhibition of endothelial progenitor cell differentiation by VEGI
Fang Tian, Paulina H. Liang, and Lu-Yuan Li*
Department of Pathology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States
College of Pharmacy, Nankai University, Tianjin, China
* Corresponding author; email: lil{at}upmc.edu.
Endothelial progenitor cells (EPC) play a critical role in post-natal and tumor vasculogenesis. Vascular endothelial growth inhibitor (VEGI; TNFSF15) has been shown to inhibit endothelial cell proliferation by inducing apoptosis. We report here that VEGI inhibits the differentiation of EPC from mouse bone marrow-derived Sca1+ mononuclear cells. Analysis of EPC markers indicates a significant decline of the expression of endothelial cell markers, but not stem cell markers, on VEGI-treated cells. Consistently, the VEGI-treated cells exhibit a decreased capability to adhere, migrate and form capillary-like structures on Matrigel. In addition, VEGI induces apoptosis of differentiated EPC but not early stage EPC. When treated with VEGI, an increase of phospho-Erk and a decrease of phospho-Akt are detected in early stage EPC, while activation of NF-
B, JNK and caspase-3 are seen in differentiated EPC. Furthermore, VEGI induced apoptosis of differentiated EPC is, at least partly, mediated by death receptor-3 (DR3), which is detected on differentiated EPC only. VEGI induced apoptosis signals can be inhibited by neutralizing antibodies against DR3 or recombinant extracellular domain of DR3. These findings indicate that VEGI may participate in the modulation of post-natal vasculogenesis by inhibiting EPC differentiation.
