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Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress

¹Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York; and ²Department of Pharmacology and ³Biocomplexity Institute, Department of Physics, Indiana University, Bloomington, Indiana

Submitted 17 March 2005 ; accepted in final form 27 April 2005

Endothelium-derived microparticles have recently been described as a new marker of endothelial cell dysfunction. Increased levels of circulating microparticles have been documented in inflammatory disorders, diabetes mellitus, and many cardiovascular diseases. Perturbations of angiogenesis play an important role in the pathogenesis of these disorders. We demonstrated previously that isolated endothelial microparticles (EMPs) impair endothelial function in vitro, diminishing acetylcholine-induced vasorelaxation and nitric oxide production by rat aortic rings and simultaneously increasing superoxide production. Herein, using the Matrigel assay of angiogenesis in vitro and a topological analysis of the capillary-like network by human umbilical vein endothelial cells (HUVECs), we investigated the effects of EMPs on formation of the vascular network. All parameters of angiogenesis were affected by treatment for 48 h with isolated EMPs in a concentration of 10⁵ but not 10³ or 10⁴ EMPs/ml. The effects included decreases in total capillary length (24%), number of meshes (45%), and branching points (36%) and an increase in mesh area (38%). The positional and topological order indicated that EMPs affect angiogenic parameters uniformly over the capillary network. Treatment with the cell-permeable SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (Mn-TBAP) partially or completely restored all parameters of angiogenesis affected by EMPs. EMPs reduced cell proliferation rate and increased apoptosis rate in time- and dose-dependent manners, and this phenomenon was also prevented by Mn-TBAP treatment. Our data demonstrate that EMPs have considerable impact on angiogenesis in vitro and may be an important contributor to the pathogenesis of diseases that are accompanied by impaired angiogenesis.

human umbilical vein; angiogenesis; diabetes; cardiovascular disease

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