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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/R467    most recent 00432.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yang, C. Articles by Hardy, P. Search for Related Content PubMed PubMed Citation Articles by Yang, C. Articles by Hardy, P.

NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Lymphocytic microparticles inhibit angiogenesis by stimulating oxidative stress and negatively regulating VEGF-induced pathways

¹Department of Pediatrics, Ophthalmology, and Pharmacology, Research Center of CHU Sainte-Justine, Montreal, Quebec; and ²Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

Submitted 19 June 2007 ; accepted in final form 27 November 2007

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 (O₂^–). 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.

NADPH oxidase; CD36; vascular endothelial growth factor receptor type 2