Lymphocytic microparticles inhibit angiogenesis by stimulating oxidative stress and negatively regulating VEGF-induced pathways.
Recent studies have demonstrated that lymphocyte-derived microparticles (LMPs) impair endothelial cell function. However, no data currently exist regarding the contribution of LMPs in the regulation of angiogenesis. In the present study, we investigated the effects of LMPs on angiogenesis in vivo and in vitro and demonstrated that LMPs strongly suppressed aortic ring microvessel sprouting and in vivo corneal neovascularization. In vitro, LMPs considerably diminished human umbilical vein endothelial cell survival and proliferation in a concentration-dependent manner. Mechanistically, the antioxidants U-74389G and U-83836E were partially protective against the antiproliferative effects of LMPs, whereas the NADPH oxidase (NOX) inhibitors apocynin and diphenyleneiodonium significantly abrogated these effects. Moreover, LMPs increased not only the expression of the NOX subunits gp91(phox), p22(phox), and p47(phox), but also the production of ROS and NOX-derived superoxide (O(2)(-)). Importantly, LMPs caused a pronounced augmentation in the protein expression of the CD36 antiangiogenic receptor while significantly downregulating the protein levels of VEGF receptor type 2 and its downstream signaling mediator, phosphorylated ERK1/2. In summary, LMPs potently suppress neovascularization in vivo and in vitro by augmenting ROS generation via NOX and interfering with the VEGF signaling pathway.
Research Center of CHU Sainte-Justine, 3175 Côte-Sainte-Catherine,Montreal, Quebec, Canada.
Chun
C
Yang
Bupe R
BR
Mwaikambo
Tang
T
Zhu
Carmen
C
Gagnon
Josiane
J
Lafleur
Swathi
S
Seshadri
Pierre
P
Lachapelle
Jean-Claude
JC
Lavoie
Sylvain
S
Chemtob
Pierre
P
Hardy
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003573:Cytochrome b Group / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008214:Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000276:immunology*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000975:Antioxidants; D018955:CD36 Antigens; D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515614:Cyba protein, mouse; C060505:neutrophil cytosolic factor 1; D040301:Vascular Endothelial Growth Factor Receptor-2